Epidermal cytokines in allergic contact dermatitis

Epidermal cytokines in allergic contact dermatitis Seiji Kondo, MD, PhD, and Daniel N. Sauder, MD, FRCPC, FACP Toronto, Canada

Ontario,

The understanding of cutaneous immunology has grown significantly during the past decade, particularly regarding the immune function of keratinocytes. Keratinocytes play a major role in immune and inflammatory reactions, mainly through synthesis and release of cytokines. The cytokine network in the skin is an important contributor to normal homeostasis and to the pathogenesis of cutaneous disease. Although cytokine dysregulation has been implicated in the pathogenesis of many cutaneous diseases,allergic contact dermatitis is one that has been the most extensively studied. The aim of this article is to provide a comprehensive current review of the mechanisms of allergic contact dermatitis with particular emphasis on the role of epidennal cytokines. (J AM ACAD DERMATOL 1995;33:786-800.)

Allergic contact dermatitis is a prototypic T-cellmediated cutaneous inflammatory response mediated by antigen-specific T lymphocytes. Multiple cell types, inflammatory mediators, and cytokines are involved in the regulation of immunologic and inflammatory processesin allergic contact dermatitis.l Keratinocytes, the first target for contact allergens, play an active role in these processes by producing an array of cytokines.2 This review discusses cellular events in allergic contact dermatitis and the pivotal role played by epidermal cytokines. CELLULAR EVENTS OF ALLERGIC CONTACT DERMATITIS

Induction phase (afferent antigen recognition)

phase, sensitization,

When a hapten (low molecular weight substances by themselves, not immunogenic) is applied to the skin, it binds covalently with skin macromolecules, “carrier proteins,” to form the hapten-carrier complex that finally acts as an immunogen (antigen).3 The antigen is processed by Langerhans cells (LCs) within the epidermis. Langerhans cells are derived from the bone marrow and can be identified by organelles (Birbeck From the Division of Dermatology, tre, University of Toronto.

Sunnybrook

Health

Science

Cen-

Supported in part by grants from the Medical Research nadian Dermatology Foundation and Health Canada.

Council,

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Reprint requests: Daniel N. Sauder, MD, FRCPC, FACP, Division of Dermatology, Sunnybrook Health Science Centxe, University of Toronto, 2075 Bayview Ave., A-319, Toronto, Ontario, Canada M4N 3M5. Copyright 0190-9622/95

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granules) in their cytoplasm and by other markers. They are the major antigen-presenting cells in the skin and have long-branching dendritic processes that form a virtually contiguous network witbin the epidermis. They express the CD1 marker: CD4 molecule (only in human beings),5 class I6 and class II major histocompatibility complex (MHC) (HLA-DR in human beings and Ia in mice),7, 8 C3R (receptor for the third component of complement),9 FcrR (receptor for Fc fragments of IgG)? and FceRI (only in human beings, high-affinity receptor for IgE)‘O, l1 and FceRII (lowaffinity receptor for IgE)12 (for a recent review of LC function see Baer13 and Gaspari14 (Table I). Within minutes of binding to LC surface structures, antigens are internalized by pinocytosis. They can be subsequently localized in intracellular membrane-bound vesicles (endosomes) in which they are partly digested into peptide fragments that can bind to MHC molecules. The complex of peptide and MHC molecule is thus formed inside the LC and is subsequently transported to LC surface membrane, where it is expressed. Antigen-bearing LCs migrate to the draining lymph nodes within 24 hours of hapten application, where they can present the antigen to naive helper T lymphocytes (Fig. 1).15-17 Many functional details about antigen-bearing LC have yet to be determined, for example, when do LCs begin to migrate, what is the stimulus, and what regulates LC migration (see later section). After contact with hapten occurs, LCs are thought to undergo morphologic changes. 18-20Their dendrites become rounded and have a reduced number of short protrnsions. This occurrence may be a prerequisite for LC movement

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from the epidermis. After reaching the draining lymph nodes, LCs return to their previous morphologic condition, which may be necessary to effectively transmit antigenic information to T cells. Changes in expression of cell adhesion molecules on LCs are also believed to be important for inducing LC migration. Cultured murine LCs (functionally similar to those migrating to lymph nodes) express lower levels of E-cadherin and exhibit decreased affinity for keratinocytes, which suggests that E-cadherin expression by LCs may be a key in keratinocyte-LC interactions and consequently a critical factor for LC migration.21 An upregulation of very late antigen (VLA)-4 (p 1-integrin) expression on activated LCs (3-day cultured LC) has been demonstrated, suggesting its possible involvement in their migration, interaction, or both with cells in the lymph node.22 Thus morphologic changes and modulations of cell adhesion molecule expression on LCs may be important factors for LC migration, but it is not known whether they are causes or effects of the complex migration phenomenon. During antigen processing and migration, LCs achieve functional maturation to be able to present specific antigenic information to naive CD4+ helper T cells (Th). This functional maturation includes abundant expression of MHC class II molecules.23 Moreover, expression of lymphocyte function-associated antigen (LFA)--3, intercellular adhesion molecule (ICAMtl, and B7 adhesion molecules on the cell surface is thought to be important because these molecules provide a system of secondary signals for antigen presentation. 24-26 CD4 molecules recognize the MHC class II on LCs, whereas the T-cell receptor (TCR) (i.e., Ti-CD3 complex, consisting of the CD3, a transducing protein found on all T cells, coupled with Ti, a heterodimeric protein, whose variable region acts as an additional antigen binding site) recognizes the processed antigen. 27As a result of antigen presentation, T-cell proliferation takes place in the paracortical region of the lymph nodes to produce effector and memory T cells (primed T cells) that are then released into the circulation.28 LC-T-cell interaction includes recognition of MHCrestricted antigen, interleukin (IL)-2 production by T cells, and the clonal expansion of memory T cells. These processes require secondary signals mediated by the following adhesion molecules and their corresponding ligands: ICAM- ULFA- 1,2g LFA-3/CD2,1g or B7/CD2830, 31 (reviewed in Springer,32 Fig. 2). A recent study demonstrated ICAM- expression on LCs and suggested that the adhesion molecule pair ICAM-

Table I. Cell surface molecules expressed on Langerhans cell Molecule

Reference

Class I MHC Class II MHC CD1 CD4” FqR (receptor for Fc fragments of IgG) C3R (receptor for the third component of complement) Fc&I (high-affinity receptor for IgE)* Fc&II (low-affiity receptor for IgE) VLA4 (CD49d) E-cadherin ICAIv- 1 (CD54) ICAMLFA-3 (CD58) B7- 1 (CD80) VU, Very late activation *Only in humans.

No.(s)

6 7, 8 4 5 9 9 10,ll 12 22 21 29 33 19 30,31

antigen.

3/LFA-1 may also be involved in the initiation phase of LC-leukocyte interactions during localized skin immune reactions.33 The afferent phase of allergic contact dermatitis is basically characterized by a significant reduction in the density of LCs at the hapten application site34 and by LC migration from the epidermis to the draining lymph nodes.35 After epicutaneous hapten application occurs, a rapid migration of LCs are seen.36-38 Elicitation

phase (efferent

phase, challenge)

The elicitation phase occurs when the antigen is reintroduced into a person previously exposed and sensitized to that antigen. This phase is more rapid than the sensitization phase. The cell-mediated hypersensitivity reaction usually takes place within 48 hours after reexposure to the contact allergen. The initial challenge sequence is identical to that of the sensitization phase, that is, formation of the hapten-carrier complex. However, during this phase antigen presentation by LCs, macrophages, or both and recognition by primed effector T cells occur in the epidermis, dermis, and in the regional draining lymph nodes (Fig. 3). Intraepidermal apposition between LCs and lymphocytes has been observed as soon as 4 to 6 hours after topical application of mercury bichloride in sensitized subjects.3g Recognition of the antigenic information by the effector T cells (CD4+ Th clones) results in blast transformation and clonal

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Afferent

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phase

T cells

Fig. 1. Cellular events in afferent phase of allergic contact dermatitis. LCs within epidermis process antigen (hapten-canier protein complex) and migrate to draining lymph nodes, where it presents antigenic information to naive CD4+ helper T lymphocytes. As a result of antigen presentation, T-cell proliferation takes place in paracortical region of lymph nodes to produce effector and memory T cells (primed T cells),which are then releasedinto circulation. o, Keratinocytes; 0, naive T cells; 0, primed T cells.

T Cell

Fig. 2. LC-T-cell interaction during antigen presentation. LC-T-cell interaction requires secondary signals mediated by adhesion molecules and their corresponding ligands (ICAM/LFA-1; LFA31CD2; B7/CD28) and recognition of MIX-restricted antigen by T-cell receptor.

proliferation with consequent release of a series of cytokines40 such as IL-2,“l interferon y (E’N-r),42 granulocyte-macrophage colony-stimulating factor (GMCSF),43 IL-3,@ and lL-4.45 CD4+ T helper clones have been categorized into two subtypes on the basis of differences in their profiles of cytokine production: Thl subtype produces E-2, IFN-y, and tumor necrosis factor (TNF)+, whereas Th2 cells produce IL-4, IL-5, E-6, IL-lo, and IL,-13; other cytokines including IL-3, GM-CSF, and TNF-(r. are produced by both Thl and Th2 cells.46 Accumulating evidence indicates the existence and im-

portance of Thl and Th2 phenotypes in human T-cell clones.47 The concept of two categories of CD4+ helper cells has been extended to CD8+ cells, some of which are known to have a helper function.48 Therefore CD4+ cells and CD8+ cells are now referred to as Tl (type 1) and T2 (type 2) cells.49T5o Type 1 CD8+ T cells produce EN-7 but not IL-4. In contrast, IL-4 is mainly produced by type 2 CD8+ T cells. Because the two

subsets of cytokines have mutually inhibitory or selfstimulatory roles, differential production of these cytokines in vivo would have a variety of effects on allergic contact dermatitis. Mouse model experiments

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Fig. 3. Cellular events in efferent phase of allergic contact dermatitis. Antigen presentation by LCs and recognition by primed effector T cells occur in epidermis and dermis and in regional draining lymph nodes. Recognition of antigenic information by effector T cells results in blast transformation and clonal proliferation with consequent releaseof a seriesof cytokines including IL-2 and IFN-y. For legend, see Fig. 1. have stressed the importance of both CD4+ and CD8+ T cells in allergic contact dermatitis.51 Certain cytokines termed ‘ ‘chemokines” are chemotactic and are believed to recruit and activate inflammatory cells. Some other cytokines such as IFN-7 and TNF-CY also have a direct effect on keratinocytes function including induction of ICAM- 1 and HLA-DR expression on keratinocytes,52, 53 which can be important in T-cell migration to epidermis. However, because the increased expression of ICAMon keratinocytes is observed earlier than dermal T-lymphocyte infiltration,54 the initial trigger for ICAM- 1 and HLA-DR expression on keratinocytes is unclear. Although LCs (antigen-presenting cells) and T lymphocytes are the major participants in allergic contact dermatitis, recent in vivo and in vitro studies indicate that mast cells and their secretory products may also be fundamental to initiation of cutaneous inflammation. Mast cell degranulation and activation occur rapidly (1 hour) after hapten challenge. Endothelial leukocyte adhesion molecule (ELAM)--1 (E-selectin) is expressed on dermal postcapillary venules in the human skin from 2 hours after challenge.56 Thus the induction of new endothelial cell surface proteins is an important early step in the development of an inflammatory infiltrate. EPIDERMAL CYTOKINES REGULATING ALLERGIC CONTACT DERMATITIS

Increasing evidence has been found that keratinocytes (approximately 90% to 95% of the cell mass

of epidermis) participate in cutaneous immunologic and inflammatory reactions by producing a variety of cytokines.2 It has been proposed that keratinocytes act as “signal transducers” capable of converting exogenous stimuli into coordination and control of the host defense and homeostatic responses.57 LCs represent only a small part of the epidermal population (2% to 5%).58 However, they play a major role in allergic contact dermatitis, as described previously. LCs, when stimulated, also express and produce several kinds of cytokines that may be centrally involved in allergic contact dermatitis. The local cytokine microenvironment within the epidermis and in the route of LC migration from the skin to the draining lymph nodes may also be important in facilitating the induction and elicitation phases of the immune responses. Moreover, a modulation of LCs may be caused by epidermal (keratinocytes and LCs) cytokines.4l Keratinocyte-derived

cytokines

Epicutaneous hapten application directly activates keratinocytes. Although resting keratinocytes synthesize and secrete low levels of cytokines, activated keratinocytes produce a variety of cytokines including ~-1 59,60 IL-3,61-63 IL464 ~~65 IL-&~ 67 ~-lo,68 granulocyte colony-stimulating factor,69 macrophage colony-stimulating factor,7o GM-CSF,71 TNF-Ix,~~ transforming growth factor+ and -p (TGF-a, TGF13)?3-75 platelet-derived growth factor (PDGF)y6 tibroblast growth factory7 and nerve growth factory8, 79

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Table II. Keratinocytes-derived Cytokine

IL-lo IL-1p

IL-10 l-N%

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cytokines affecting allergic contact dermatitis response in vivo Effects on allergic contact dermatitis

Reduces allergic contact dermatitis SuppressesLC antigen-presenting function Suppressesallergic contact dermatitis when applied during sensitization Enhances allergic contact dermatitis when applied 48 hours before challenge Suppressesallergic contact dermatitis when applied 2 hours .before challenge Promotes the induction of allergic contact dermatitis by upregulating MHC class II molecules on LC Regulates the duration of allergic contact dermatitis Prevents the elicitation of allergic contact dermatitis Induces accumulation of dendritic cells in draining lymph nodes Suppressessensitization by impairing the function of LC Impairs induction and amplification of allergic contact dermatitis Causes morphologic damage to LC

This review focuses on evidence for the role of certain cytokines in allergic contact dermatitis (Table II).

IL-1 IL-l was the first cytokine demonstrated to be produced by keratinocytes?9* 60 Keratinocytes can spontaneously release IL-1 and express messenger RNA (mRNA) for both IL-lo and IL-l 13.80In contrast to macrophages, which mainly produce IL- 1p, the predominant active IL-l species released from keratinocytes is IL-la. 8o This may be because pro-IL-l@ (biologically inactive 3 1 kd IL- 1 p) has to be cleaved into the active 17 kd form by a specific protease (IL- 1p convertase) that is not present in keratinocytes.81 In contrast, 3 1 kd IL- lo can bind to the IL- 1 receptor and is biologically active. Within normal epidermis IL-la and IL-1 l3 are located at the membrane level or in the intercellular space,82 which represents a physiologic reservoir of this interleukin in the ~kin.*~ Although IL-la production is constitutively present in normal keratinocytes, preformed IL-la and IL-l@ as well as newly synthesized IL-la are released or produced after activation. Released pro-IL- 1p may be converted by specific protease activities released by other cells.81 IL-1 may participate in the regulation of local and systemic immunologic and inflammatory reaction not only directly but also secondarily through promotion of release of other cytokines such as IL-6,s4 lL-,8,85 and GM-CSFg6 from neighboring keratinocytes. One of the in vitro roles identified for lL-1 is its ability to enhance LC functional activity (induction of Ia molecule expression) when used together with GM-CSF.87-89 IL-1 also activates helper T cells to secrete IL-2 and express IL-2 receptor in vitro, thus lead-

I

Reference No.

91 95 90 90 90 94

191 191-194 111 112,113 114 . 115

ing to autocrine stimulation and proliferation of those cellss9 The role of IL-l in allergic contact dermatitis is a topic of major investigation. IL-1 is one of many cytokines produced during allergic contact dermatitis.57 Although IL- 1 has the potential to mediate events in the allergic contact dermatitis response, its primary role in this disease has not been established. Systemic administration of recombinant human IL-lfl to mice undergoing allergic contact dermatitis demonstrated that this cytokine affects the two phases (sensitization and elicitation) of allergic contact dermatitis differently.” IL-l/3 caused a net suppression of the fmal allergic contact dermatitis response when it was administered during the sensitization phase, whereas its administration before challenge caused enhancement (48 hours before challenge) or suppression (2 hours before challenge) of the reaction. 9o In contrast, another study showed that the systemic administration of IL-1 reduced murine allergic contact dermatitis responses.g1 Our recent finding that IL-1 receptor antagonist significantly impairs the sensitization and challenge phases of allergic contact dermatitis* emphasizes the role of IL-l as a potentiator of responses associated with allergic contact dermatitis. LCs are considered a target for IL-1 activity in the skin. It has been shown that IL-1 acts on cultured LCs, not only increasing their viability but also enhancing their ability to activate allogeneic T cells when applied in conjunction with GM-CSF.87 Several reports sug*Kondo S, Pastore S, Fujisawa H, et al. Interleukin-1 receptor antagonist suppresses contact hypersensitivity. .I Invest Dematol (In press.)

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gest that significant changes in IL- 1B gene expression in LCs correlate with their functional activation as potent antigen-presenting cells both in vitro and in situ. IL- 1 B mRNA expression appeared to be gradually but strongly upregulated during the 3-day LC culture period, and this phenomenon has been considered specifically inherent to the maturation of cultured LCs into potent stimulator-y dendritic cells.g2 A similar change in IL-1B gene expression was observed in LC in situ after topical application of contact sensitizer.g3 These authors also demonstrated that IL-la and IL- 1B exerted a different control on allergic contact dermatitis reactions. Through evidence derived from in vivo and in vitro studies, they showed that only IL-1B plays a major role in the induction phase of allergic contact dermatitis.94 Intrademral administration of recombinant murine IL-l B uniquely caused changes in expression of cytokine n-RNA in the epidermis that were similar to those resulting from topical application of a hapten. IL-l B but not IL-lo was shown to upregulate MHC class II molecule expression on LCs in situ, again promoting the induction of allergic contact dermatitis. Moreover, intradennal injection of anti-IL-1B monoclonal antibody (mAb) prevented an effective sensitization of mice to trinitrochlorobenzene.94 IL- 1(x may be an important suppressive regulator of LC antigenpresenting function in the classic delayed-type hypersensitivity (DTH) murine mode1.95 All responses to IL- 1 are mediated by IL- 1 receptors expressed on target cells, and biologic effects of IL-l are inhibited by IL-l receptor antagonist and soluble IL- 1 receptor. IL-1 receptor antagonist was initially reported to bind with high affinity to the 80 kd type I receptor, expressed on T cells, endothelial cells, keratinocytes, hepatocytes, and fibroblasts.96 Subsequent studies have shown that it can also recognize the 68 kd type Il receptor present on neutrophils, B cells, bone marrowderived cells, and activated keratinocytes.97 The importance of the balance between IL- 1 and IL- 1 receptor antagonist, IL-l receptors, or soluble IL-l receptor in the course of allergic contact dermatitis will be discussed later. The other important role for IL- 1[x and IL- 1B is induction of adhesion molecules. ICAM- 1, vascular cell adhesion molecule-l, and ELAM-1 expression on endothelial cells and LFA-3 expression on lymphocytes or endothelial cells are induced by IL-1 and TNF-o~.~*-~~~These adhesion molecules are related to leukocyte-endothelial adhesion and recruitment of inflammatory cells in the site of reaction.104-107 Recent observations indicate that a unique skin-associated

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subset of circulating memory T lymphocytes uses ELAM-1 to initiate their process of extravasation.56, ro8,‘09 IL-l also enhances vascular permeability by activating phospholipase followed by arachidonic acid release for prostaglandii and leukotriene production from keratinocytes. These eicosanoids directly produce vasodilation or secondarily affect vascular permeability through mast cell activation and consequent release of histamine, prostaglandin, leukotriene, and platelet activating factor.

TNF--a TNF-a is believed to be important in the early events of allergic contact dermatitis. TNF-cw enhances cellular integrity of cultured LCs and maintains cell viability, although it does not affect LC functional maturation. ‘lo The observation that dermal injection of TNF-(x led to accumulation of dendritic cells in draining lymph nodes”’ led to the hypothesis that TNF-(x serves as a stimulus for the migration of LCs from skin to lymph nodes. Other investigators have postulated a suppressive role of TN?-CX. From studies on (UVB) immunosuppressive effects on contact hypersensitivity, Kurimoto and Streilen’ l2 and Streilein’ l3 proposed that local release of TNF-ar, caused by isomerization of epidermal tram-urocanic acid to its biologically active &-form, suppresses sensitization by its ability to impair the function of epidermal LCs. They also demonstrated that local application of TN?% leads to impaired induction and amplification of allergic contact dermatitis. ’ l4 Moreover, TNF-cx seems to cause morphologic damage to LCs and induces an inability to mount a normal contact hypersensitivity response. 1l5 Immunohistologic studies have shown that keratinocyte expression of TNF-cx was not significantly altered in the allergic patch test reaction induced by nickel sulfate compared with untreated control specimens. ‘16 In contrast, studies of human serial biopsy specimens of allergic contact dermatitis induced by poison ivy/oak extract demonstrated an early (within 4 to 8 hours) expression of TNFo and ICAM- on keratinocytes.117 Controversial results were also obtained with respect to the blocking effect of anti-TNF-a mAb in a murine allergic contact dermatitis model. Although systemic administration of anti-TNF-mAb before challenge seemed to abrogate allergic contact dermatitis according to one group of researchers,“’ another showed that anti-TNF-mAb is effective only for allergic contact dermatitis inhibition during the afferent or priming phase of immunity and is ineffective during the effer-

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ent phase.l” A recent review summarized the role of TNF-a in inflammation and immunologic reaction as either beneficial (protective) or deleterious (pathologic) depending on timing, target cells, and magnitude of the inflammatory reaction.120 Like IL-l, TNF-(x also induces several kinds of adhesion molecules including ICAM-l,121 vascular cell adhesion molecule-l ,to2 ELAM- 1,122and LFA-3123 on endothelial cells. Exogenous TNF-(x causes a slight increase in the level of ICAM- 1 expression on cultured LCs 124TNF-cx induces degranulation of human dermal mast cells in vitro,125 eventually leading to the release of a number of mediators including many cytokines (IL-l, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, GM-CSF, TNF-a, TNF-p, EN-y, and chemokines). Although no direct evidence exists, these observations indicate the possibility that mast cell activation contributes to the induction and maintenance of the inflammatory infiltrate. Further studies are needed to elucidate the precise role of endogenous TNF-a during the response to a contact allergen. Preliminary results with TNF-receptor (IN?-R) gene-deficient mice126 suggested that TNF may play a suppressive role in allergic contact dermatitis (unpublished data). GM-CSF GM-CSF contributes to maintaining viability and increasing the immunostimuIatory function of cultured LC.‘” Although freshly isolated LCs induce a vigorous proliferative response in primed alloreactive T cells, they are poor stimulators of a primary mixed epidermal cell-lymphocyte reaction. In contrast, LCs isolated from 2- to 4-day epidermal cell cultures and freshly isolated LCs cultured for 3 days in the presence of the cytokines GM-CSF and IL- 1 act as potent stimulators for both the primary and secondary primary epidermal cell-lymphocyte reaction.88 Their functional maturation is accompanied by a number of phenotypic changes including elevated expression of Ia antigen 12* and B7 molecule.129 Furthermore, the combination of GM-CSF and TNF-0~ induces the differentiation of human hematopoietic progenitor cells purified from cord blood into cells displaying the morphologic condition, phenotype, and function of LCs.13’ In vivo experiments with anti-GM-CSF mAb showed its partial inhibitory effect when mAb was used in combination with anti-IL-3 mAb on the elicitation phase in a murine allergic contact dermatitis rnodel.l18 IL-6 IL-6 is a major mediator of the acute phase response, because it enhances the production of acute phase pro-

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teins.‘“’ The important role of IL-6 in inflammation is also supported by recent fmdings showing increased IL-6 plasma levels after elicitation of allergic contact dermatitis in mice.132 Another study showed an increase in keratinocyte-bound IL-6 in allergic patch test reaction sites.’ l6 IL-6 also plays a role in the local control of LC number and function.12g, 133IL-6, like IL- 1, is also able to function as a second signal required for thymocyte and T-cell proliferation.15 These cytokines have important proinflammatory and immunoregulatory properties. However, do these epidermal cytokines cross the basement membrane and influence cellular components situated in the dermal portion, and to what extent do dermal cytokines contribute to the regulation of the events occurring in the epidermis? Recently, Katz and Tai~hmar$~~ demonstrated that cytokines can go from the epidermis into the dermis in an in vitro two-chamber culture model. However, under some inflammatory conditions other factors including proteolytic enzymes may affect the stability of cytokines. Keratinocyte-derived cytokines may possibly play an important role in the epidermis and have some effects on LCs and on dermal components, but little is known in terms of cytokine receptor expression on LCs and their regulation, and it is also unclear whether keratinocyte-derived cytokines could affect complete LC maturation from immature precursors in situ. LC-derived

cytokines

Despite the importance in clarifying their roles in allergic contact dermatitis, much remains to be determined concerning the production and regulation of LC-derived cytokines. LCs in the immature stage (similar to freshly isolated LCs, which have processing function and express Ia antigen) express macrophage inflammatory protein (MIP)-lo, IL-1 B, and MB?-2 mRNA, but in the mature stage (similar to 3-day cultured LCs, because they are able to activate resting T cells but do not have a processing function) they show lower expression of MIPS but upregulation of IL- 1B mRNA.92 Other studies have demonstrated that cultured LCs synthesize and secrete IL-1B and IL-6.135 After stimulation by phorbol myristate acetate and lipopolysaccharide, LCs release TNF-(x. 136 Several studies demonstrated that LCs are a major or even the only source of IL-1 B in mouse epidermis,92, 137whereas in human epidermis both keratinocytes and LCs clearly express IL-1B mRNA.80, 81,13*, 139 Enk and Katz93 demonstrated that exogenous IL- 1B causes enhancement of mRNA signals for varying cytokines, mim-

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icking the changes caused by a contact allergen. They also showed that LC-derived IL- 1p signals are the earliest changes in the epidermis after antigen application. They concluded that LC-derived IL-l l3 is a critical mediator in the primary immune response of allergic contact dermatitis.94 In contrast, a recent report demonstrated IL-lo in LC plasma membrane and suggested that this cytokine may play a role in activating the antigen-presenting capacity in the initiation of immune responses. 139 Despite the finding that phorbol my&ate acetate and lipopolysaccharide stimulate LCs to release of TNF-(x, it has not yet been shown that LC-derived TNF-cx affects LC viability and migration in vivo. At present the exact role of LC-derived cytokines in allergic contact dermatitis is unclear. OTHER CYTOKINES REGULATING ALLERGIC CONTACT DERMATITIS The interaction of allergens with epidermal cells and activated keratinocyte-derived, LC-derived cytokines, or both and their direct or indirect effects on LC may be of significant importance for induction of immune responses. Mast cells may also contribute significantly to the inflammatory cascade140 because they are an abundant source of cytokines (IL-l, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, GM-CSF, TNF-a, TFG-l3, IFN-y, and chemokines)‘41-‘45 and chemical mediators (histamine, prostaglandin, leukotriene and platelet-activating factor)146-149 because of their location in the dermis, where they can directly affect endothelial cells to express cell-adhesion molecules and increase vascular permeability.‘o Human mast cells release TNF-cx when activated, and this occurrence has been linked to increased expression of E-selectin in adjacent endo~e~~.150,

151

In terms of the mast cell requirement for the classical DTH reaction (as apposed to allergic contact dermatitis), there are two seemingly contradictory reports based on studies in mast’ cell-deficient mutant mice. 15~,153The first report demonstrated by adoptive transfer experiments that the ability to elicit DTH can be transferred to normal mice with sensitized T cells from mast cell-deficient mice but that sensitized T cells from normal mice cannot transfer DTH responsiveness to mast cell-deficient mice. Furthermore, these mast cell-deficient mice exhibit no defects in numbers of epidermal LCs or in antigen-presenting cell function.152 The second report demonstrated a successful induction of DTH reactions in these mast cell-deficient mice.153 These two reports seem contradicting, but the

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first demonstrated the inability of the mutant mice to serve as recipients for systemic passive transfer of DTH, and the second demonstrated the ability of the mutant mice to have DTH. The general belief is that although mast cells may not be indispensable in allergic contact dermatitis, they probably exert a modulatory effect. In addition to mast cells, basophils and eosinophils are also observed in the dermal infiltrate in allergic contact dermatitis. Human peripheral blood eosinophils stimulated in vitro express mRNA and immunoreactivity for GM-CSF, IL-la, IL-3, IL-5, IL-6, and TGF,154-157whereas cytokine production by basophils has not yet been clearly elucidated. Elucidation of the contributions provided by these cells to allergic contact dermatitis cytokine network is of great importance.158 It may be that the diverse and overlapping proinflammatory effects of these cytokines can be expected to amplify the inflammatory response. Although the central involvement of LCs in the sensitization process and the final memory T-cell production are major events in allergic contact dermatitis, the whole process may be affected by various cytokines produced by epidermal and dermal components. 159 In the final amplification phase, effector T cells leave the intravascular space, enter the skin tissues, and become activated by antigen presentation to release many chemoattractant cytokines and eventually recruit a nonspecific infiltrate of inflammatory cells. THERAPEUTIC

POSSIBILITIES

A comprehensive review of current therapeutic options has recently been reported by Funk and Maibach.160 The following discussion focuses on further therapeutic considerations. From our understanding of the cellular events and the regulatory functions of cytokines in allergic contact dermatitis, agents that can block the action of cytokine or cell adhesion molecule may have therapeutic potential. Targeting the elicitation phase of allergic contact dermatitis is of major importance because the vast majority of persons are already sensitized. Agents with an antagonistic activity on cytokines could include specific antibodies, soluble receptors, and receptor antagonists.16t Other therapeutic tools could involve use of antibodies against specific cell adhesion molecule (in a murine model, we were able to significantly reduce allergic contact dermatitis by anti-LFA- 1 antibody162) and the local administration of cytokines with immunosuppressive activity such as IL-10 or TGF-P. However, few studies have been performed to examine the

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effect of local administration of these agents on allergic contact dermatitis. Antagonists

of cytokines

The importance and usefulness of cytokine antagonists were discussed and summarized in a recent review article. 163 IL-l receptor antagonist/soluble IL-1 receptor. IL-1 receptor antagonist is a new member of the IL-1 family. l@ It is produced by the same cells that produce IL- 1 and binds competitively to IL- 1 receptors without stimulating target cells. 165,166 Soluble IL-1 receptor exerts the same function by binding IL-1 before it can interact with cell receptors.167 Administration of IL-l receptor antagonist or soluble IL-1 receptor to animals reduces the severity of inflammation in some pathologic processes. 16*-170Arecent clinical trial also showed that human cutaneous allergic late-phase response is inhibited by soluble IL-1 receptor.171 Furthermore, a regulatory role of endogenous IL-1 receptor antagonist on the biologic activity of IL-l produced in acute inflammation was demonstrated in a rabbit model of immune coliti~.‘~~ All of these suggest that the balance between IL-1 and IL-1 receptor antagonist or IL-1 receptor influences inflammatory and immunologic reactions. However, no study has been done on the effect of these molecules on allergic contact dermatitis. Anti-TNF-antibody/soluble TNF-R. Both antiTNF mAb and soluble TNF-R may be developed as therapeutic tools. 173 Although the systemic administration of anti-TNF mAb showed divergent effects on allergic contact dermatitis,1 18,’ l9 and local application of TNF-a was shown to impair allergic contact dermatitis,’ lo the effects of local administration of anti-TNF mAb and soluble TNF-R should be examined. Anti-cell

adhesion

molecule

antibodies

Anti-LFA-1 mAb. Local application of anti-LFA-1 mAb showed suppressive effects on allergic contact dermatitis in the elicitation phase in a murine mode1.t’j2 The importance of cell adhesion molecules in inflammation in vivo has been demonstrated by several studies. Inflammation within pulmonary tissue was abrogated by antibodies directed against LFA-1 and one of the ligands, ICAM- 1.174The same combination of antibodies against LFA- 1 and against one of the ligands, ICAM-1, has been shown to suppress an immune response against a cardiac allograft in rnice.175 Other in vitro studies demonstrated the suppressive or preventive effects of anti-LFA-1 mAb on graft-versus-host disease, cerebral malaria, and DTH’76, 177The mech-

of Dermatology November 1995

anisms for the suppressive effect on allergic contact dermatitis may be as follows. Anti-LFA-1 mAb blocks LC-memory T-cell binding, thus impeding communication of antigenic information and subsequent recruitment of the effector cells. Anti-LFA- 1 mAb interferes with the adhesion between leukocytes and endothehum. Anti-LFA-1 mAb blocks cell-cell interactions, thus impairing the release of early cytokines, chemical mediators, or both from leukocytes or mast cells. AntiLFA-1 mAb blocks epidermotropic migration of T cells. Anti-ELAM-1 mAb. The observation that in human skin ELAM-1 expression appears on dermal postcapillary venules from 2 hours after cutaneous challenge with dinitrochlorobenzenes6 may imply a possible therapeutic use for anti-ELAM-1, but a local administration study has never been done. Immunosuppressive

cytokines

TGF-P. TGF-B has recently been identified as an inhibitor of immune reactions. Its mechanism of action includes downregulation of IL-1 receptor expression and block of the biologic activities of IL-l, IL-2, and colony-stimulating factors.178, 179 Moreover, TGF-B has been shown to inhibit in vitro upregulation of Ia antigen expression on LC surface when promoted by IL-l, TNF-a, IEN-?, IL-3, and GM-CSF.179 In vivo administration of TGF-B into mice has an inhibitory effect on the elicitation phase of allergic contact dermatitis,18o suggesting the possible importance of an antagonism between TGF-B and other cytokines. A recent study demonstrated an exclusive cascade in monocyte cytokine production that exhibits induction of IL- 1B followed by IL- 1 receptor antagonist production after exposure to TGF-B. This report suggests that TGF-B-induced immunosuppression is caused in part by IL-l receptor antagonist. IL-lo. IL-10 was originally described as a Th2 cell-derived cytokine that inhibits the cytokine release by Thl cells.igl In vitro IL-10 inhibits production of cytokines at both mRNA and protein levels by murine Thl clones stimulated by antigen or CD3 antibody in the presence of macrophages.lg23 lg3 Further investigations have demonstrated that IL-10 maintains the viability of B cells in vitro, lg4 induces class II MHC antigen expression on B cells,ls5 and enhances mast cell proliferation. lg5 IL-10 also strongly inhibits dendritic cell-induced IEN- production by Thl cell clonelg6 and the production of IL-l, IL-6, IL-8, TNF-a, and GM-CSF by T cells, monocytes, and activated macrophages .lg7, lg8 IL-10 also prevents antigen-specific T-

Journal of the American Academy of Dermatology Volume 33, Number 5, Part 1

cell proliferation by inhibition of monocyte antigenpresenting capacity via downregulation of MHC class II expression. lg9 Recent studies have shown that murine keratinocytes are capable of producing IL-10 mRNA and protein during the induction phase of allergic contact dermatitis,19o suggesting that endogenous IL-10 may play a role in allergic contact dermatitis. Ferguson et al. 19r demonstrated that locally produced IL- 10 after antigenic challenge regulates the duration of allergic contact dermatitis response and the application of exogenous IL-10 into the skin before antigenic challenge prevents the elicitation of allergic contact dermatitis in previously sensitized mice. The suppressive role of exogenous IL-10 in immunologic phenomena in vivo demonstrated by several other goups192-194 suggests IL-10 as a therapeutic tool. CONCLUSION

In the epidermis keratinocyte-derived and LCderived cytokines may serve an important function by affecting LC function and mobility. In the dermis mast cell-derived cytokines and mediators may be important in inflammatory reactions. Moreover, leukocytes, activated endothelial cells, and fibroblasts can also release various cytokines. All these components can affect each other to form a complex cytokine network in the skin. Epidermal cells produce various kinds of cytokines, but it is important to elucidate the extent to which these cytokines affect inflammatory and immunologic phenomena in the skin and also the way in which they are regulated in the complex cytokine cascade in the skin. A number of approaches including enzyme-linked immunosorbent assay for measurement of cytokine levels, immunohistochemical and in situ hybridization for investigating the presence of cytokines within tissues, and reverse transcriptase-polymerase chain reaction for the detection of cytokine mRNA should be used complementarily in the investigation of the role of cytokines in allergic contact dermatitis. Furthermore studies in cytokine gene-deficient (gene-knockout) mice will provide useful information regarding the actual involvement of each molecule in the immunologic and inflammatory processes in allergic contact dermatitis. REFERENCES 1. Sauder DN, Pastore S. Cytokines in contact dermatitis. Am J Contact Dermatitis 1993;4:215-24. 2. Kupper TS. Mechanisms of cutaneous intlammation. Arch Dermatol 1989;125:1406-12. 3. Eisen HN, Orris L, Belman S. Elicitation of delayed skin re-

Kondo and Sauder

4.

5.

6.

7. 8. 9. 10. Il. 12.

13. 14. 15. 16.

17. 18. 19.

20. 2 1. 22.

23.

795

actions with haptens: the dependence of elicitation on hapten combination with protein. J Exp Med 1952;95:473-85. Schmitt D, Dezutter-Dambuyant C, Brochier J, et al. Subclustering of CD1 monoclonal antibodies based on the reactivity on human Langerhans cells. Immunol L&t 198612: 231-5. Dezutter-Dambuyant C, Schmitt DA, Dusserre N, et al. Trypsin-resistant gp120 receptors are upregulated on shortterm cultured human epidermal Langerhans cells. Res Vim1 1991;142:129-38. Bronstein BR, Murphy GF, Ha&t TJ, et al. Location of HLA-A, B, C antigens in dendritic cells of normal human skin an immunoelectron microscopic study. J Invest Dermato1 1983;80:481-4. Rowden G, Lewis MG, Silhvan AK. Ia antigen expression on human epidermal Langerhans cells. Nature 1977;268:247-8. Klareskog L, Mahnnas-Tjernlund U, Forsum U, et al. Epidermal Langerhans cells express Ia antigens. Nature 1977; 268:248-50. Sting1 G, Wolff-Schreiner EC, Pichler WJ, et al. Epidermal Langerhans cells bear Fc and C3 receptors. Nature 1977; 2681245-6. Bieber T, de la Salle H, Wollenberg A, et al. Human epidermal Langerhans cells express the high affinity receptor for immunoglobuhn E (FceRI). J Exp Med 1992;175:1285-90. Wang B, Rieger A, Kilgus 0, et al. Epidermal Langerhans cells from normal human skin binds monomeric IgE via Fc&I. J Exp Med 1992;175:1353-65. Bieber T, Rieger A, Neuchrist C, et al. Induction of Fc&2/ CD23 on human epidermal Langerhans cells by human recombinant interleukin 4 and y interferon. J Exp Med 1989;170:309-14. Baer RL. Allergic contact dermatitis and Langerhans cells: comments on recent development. Cutis 1993;52:270-2. Gaspari AA. Advances in the understanding of contact hypersensitivity. Am J Contact Dermatitis 1993;4:138-49. Kimber I, Cumberbatch M. Dendritic cells and cutaneous immune responses to chemical allergens. Toxic01 Appl Pharmacol 1992;117:137-46. Kripke ML, Munn CG, Jeevan A, et al. Evidence that cutaneous antigen-presenting cells migrate to regional lymph nodes during contact sensitization. J Immunol 1990; 145:2833-8. Kalish RS. Recent developments in the pathogenesis of allergic contact dermatitis. Arch Dermatol 1991;127:155863. Bos JD, Kapsenberg ML. The skin immune system. Immuno1 Today 1986;7:235-40. Teunissen MBM, Wormmeester J, Krieg SR, et al. Human epidermal Langerhans cells undergo profound morphologic and phenotypical changes during in vitro culture. J Invest Dermatol 1990;94:166-73. Larsen CP, Steinman RM, Winner-Pack M, et al. Migration and maturation of Langerhans cells in skin transplants and explants. J Exp Med 1990;172:1483-93. Tang A, Amagai M, Granger LG, et al. Adhesion of epidermal Langerhans cells to keratinocytes mediated by E-cadherin. Nature 1993;361:82-5. Aiba S, Nakagawa S, Ozawa H, et al. Up-regulation of alpha 4 integrin on activated Langerhans cells relating to their migration from skin to draining lymph nodes. J Invest Dermato1 1993;100:143-7. Shimada S, Caughman SW, Shanow SO, et al. Enhanced antigen-presenting capacity of cultured Langerhans cells is associated with markedly increased expression of Ia antigen. J Immunol 1987;139:2551-5.

Journal

796

Kondo and Sauder

24. Davignon D, Martz E, Reynolds T, et al. Monoclonal antibody to a novel lymphocyte function-associated antigen (LFA-1): mechanism of blocking T lymphocyte-mediated killing and effects on other T and B lymphocyte functions. J Immunol 1981;127:590-5. 25. Dougherty GJ, Murdoch S, Hogg N. The function of human intercellular adhesion molecule- 1 (ICAM- 1) in the generation of an immune response. Eur J Immunol 1988;18:35-9. 26. Bierer BE, Barbosa J, Herrmann S, et al. Interaction of CD2 with its ligand, LFA-3, in human T cell proliferation. J Inmunol 1988;140:3358-63. 27. Reinherz EL, Meuer SC, Schlossman SF. The delineation of antigen receptors on human T lymphocytes. Immunol Today 1983;4:5-9. 28. Gajewski TF, Schell SR, Nau G, et al. Regulation of T cell activation: differences among T-cell subsets. Immunol Rev 1989;111:79-110. 29. Cumberbatch M, Peters SW, Gould SJ, et al. Intercellular adhesion molecule-l (ICAM-1) expression by lymph node dendritic cells: comparison with epidermal Langerhans cells. Immunol Lett 1992;32:105-10. 30. Symington FW, Brady W, Linsiey PS. Expression and function of B7 on human epidermal Langerhans cells. J Immunol 1993;150:1286-95. 3 1. Galvin F, Freeman GJ, Razi-Wolf Z, et al. Murine B7 antigen provides a sufficient costimulatory signal for antigenspecific and MHC-restricted T cell activation. J Immunol 1992;149:3802-8. 32. Springer TA. Adhesion receptors of the immune system. Nature 1990;346:425-34. 33. Acevedo A, de1 Pozo MA, Arroyo AG, et al. Distribution of ICAM-3bearing cells in normal human tissues: expression of a novel counter-receptor for LFA-1 in epidermal Langerhans cells. Am J Path01 1993;143:774-83. 34. Silberberg-Sinakin I, Thorbecke GJ, Baer RL, et al. Antigenbearing Langerhans cells in skin, dermal lymphatics, and in lymph nodes. Cell Immunol 1976;25:137-51. 35. Macatonia SE, Edwards AI, Knight SC. Dendritic cells and the initiation of contact sensitivity to fluorescein isothiocyanate. Immunology 1991;74:139-45. 36. Kinnaird A, Peters SW, Foster JR, et al. Dendritic cell accumulation in the draining lymph nodes during the induction phase of contact allergy in mice. Int Arch Allergy Appl Immunol 1989;89:202-10. 37. Cumberbatch M, Kimber I. Phenotypic characteristics of antigen-bearing cells in the draining lymph nodes of contact sensitized mice. Immunology 1990;71:404-10. 38. Kimber I, Kinnaird A, Peters SW, et al. Correlation between lymphocyte proliferative responses and dendritic cell migration in regional lymph nodes following skin painting with contact-sensitizing agents. Int Arch Allergy Appl Immunol 1990;93:47-53. 39. Silberberg I, Baer RL, Rosenthal SA. The role of Langerhans cells in allergic contact hypersensitivity: a review of findings in man and guinea pigs. J Invest Dermatol 1976;66:210-7. 40. Baadsgaard 0, Wang T. Immune regulation in allergic and it&ant skin reactions. Int J Dermatol 1991;30:161-72. 41. Morgan DA, Ruscetti FW, Gallo R. Selective in vitro growth of T lymphocytes from normal human bone marrows. Science 1976;193:1007-8. 42. Herberman RB, Ortaldo JR, Timonen T, et al. Interferon and natural killer (NK) cells. Tex Rep Biol Med 198 1;41:590-5. 43. Lee K, Yokota T, Otsuka T, et al. Isolation and characteriza tion of a mouse interleukin cDNA clone that express B-cell stimulatory factor I activities and T-cell and mast cell stimulating activities. Proc Nat1 Acad Sci U S A 1986;83:2061-5.

of the American

Academy

of Dermatology November 1995

44. Suzuki R, Suzuki S, Takahashi T, et al. Production of a cytokine with interleukin 3-like properties and cytokine-dependent proliferation in human autologous mixed lymphocyte reaction. J Exp Med 1986;164:1682-99. 45. Paliard X, de Waal MR, Yssel H, et al. Simultaneous production of IL-2, IL-4, and IFN-gamma by activated human CD4+ and CD8+ T cell clones. J Immunol 1988;141:849-55. 46. Fitch FW, McKisic MD, Lancki DW, et al. Differential regulation of murine T lymphocyte subsets. Annu Rev Immunol 1993;11:29-48. 47. Romaghani S. Human THl and TH2 subsets: doubt no more. Immunol Today 1991;12:256-7. 48. Kung JT, Castillo M, Heard P, et al. Subpopulation of CD8+ cytotoxic T-cell precursors collaborate in the absence of conventional CD4+ helper T-cells. J Immunol 1991;146:178390. 49. Bloom BR, Salgame P, Diamond B. Revisiting and revising suppressor T cells. Immunol Today 1992,13:131-6. 50. Salgame P, Abrams JS, Clayberger C, et al. Differing lymphokine profiles of functional subsets of human CD4 and CD8 T cell clones. Science 1991;254:279-82. 51. Gocinsky BL, Tigelaar RE. Roles of CD4+ and CD8+ T cells in murine contact sensitivity revealed by in vivo monoclonal antibody depletion. J Immunol 1990;144:1421-8. 52. Basham TY, Nickoloff BJ, Merigan TC. Recombinant gamma interferon induces HLA-DR expression on cultured human keratinocytes. J Invest Dermatol 1984;83:88-90. 53. Griffiths CEM, Voorhees JJ, Nickoloff BJ. Characterization of intercellular adhesion molecule-l and HLA-DR expression in normal and inflamed skin: modulation by recombinant gamma interferon and tumor necrosis factor. J AM ACAD DERMATOL 1989;20:617-29. 54. Griffiths CE, Nickoloff BJ. Keratinocyte intercellular adhesion molecule-l (ICAM-1) expression precedes dermal T lymphocytic infiltration in allergic contact dermatitis (Rhus dermatitis). Am J Path01 1989;135:1045-53. 55. WalshLJ, Lavker RM, Murphy GF. Determinants of immune cell trafficking in the skin. Lab Invest 1990;63:592-600. 56. Wardorf HA, Walsh LJ, Schechter NM. Early cellular events in evolving cutaneous delayed hypersensitivity in humans. Am J Path01 1991;138:477-86. 57. Barker JNWN, Mitra RS, Grifliths CEM, et al. Keratinocytes as initiators of inflammation. Lancet 1991;337:21 l-4. 58. Katz SI, Tamaki K Sachs DH. Epidermal Langerhans cells are derived from cells originating in bone marrow. Nature 1979;282:324-6. 59. Luger TA, Stadler BM, Katz SI, et al. Epidermal cell (keratinocyte) derived-thymocyte-activating factor (,ETAF). J Immunol 1981;127:1493-8. 60. Sauder DN, Carter CS, Katz SI, et al. Epidermal cell production of thymocyte activating factor (ETAF). J Invest Dermato1 1982;79:34-9. 61. Luger TA, K&k A, Kimbauer R, et al. Keratinocyte-derived interleukin 3. Ann N Y Acad Sci 1989;548:253-61. 62. Kupper TS, Horowitz M, Birchall N, et al. Hematopoietic, lymphopoietic, and proinflammatory cytokines produced by human and murine keratinocytes. Ann N Y Acad Sci 1989; 548:262-70. 63. Kondo S, Ciarletta A, Turner KJ, et al. Failure to detect interleukin (IL-3 mRNA or protein in human keratinocytes: antibodies to granulocyte macrophage-colony stimulating factor or IG6 (but not II-3) neutralize “IL-3” bioactivity. J Invest Dermatol 1995;104:335-9. 64. Kimbauer R, Kock A, Schwarz T, et al. IFN-B2, B cell dif ferentiation factor 2, or hybridoma growth factor (IL-6) is

Journal of the American Academy of Dermatology Volume 33, Number 5, Part 1

65. 66.

67. 68. 69. 70.

71.

72.

73. 74.

75. 76. 77. 78.

79. 80.

8 1. 82.

83. 84.

expressed and released by human epidermal cells and epidermoidcarcinomacelllines. JImmunol1989; 142: 1922% Heufler C, Young D, Peschel G, et al. Murine keratinocytes express interleukin-7 [Abstract]. J Invest Dermatol 1990; 94534. Larsen CG, Anderson AO, Oppenheim JJ, et al. Production of interleukin-8 by human dermal fibroblasts and keratinocytes in response to interleukin-1 or tumor necrosis factor. Immunology 1989;68:31-6. Kondo S, Kono T, Sauder DN, et al. II-8 gene expression and production in human keratinocytes and their modulation by UVB. J Invest Dermatol 1993;101:690-4. Enk AH, Katz SI. Identification and induction of keratinocyte-derived B-10. J Immunol 1992,149:92-5. Denburg JA, Sauder DN. Granulocyte colony stimulating activity derived from human keratinocytes. Lymphokine Res 1986;5:261-74. Chodakewitz JA, Lacy J, Coleman DL. Macrophage colony stimulating factor production by murine and human keratinocytes: enhancement by bacterial lipopolysaccharides. J Immunol 1990;144:2190-6. Gallo RL, Staszewski R, Sauder DN, et al. Regulation of GM-CSF and IL-3 production from the murine keratinocyte cell line Pam 212 following exposure to ultraviolet radiation. J Invest Dermatol 1991;97:203-9. K&k A, Schwarz T, Kimbauer R, et al. Human keratinocytes are a source for tumor necrosis factor CK:evidence for synthesis and release upon stimulation with endotoxin or ultraviolet light. J Exp Med 1990;172:1609-14. Coffey RJ, Derynck R, Wilcox JN, et al. Production and autoinduction of transforming growth factor-o in human keratinocytes. Nature 1987;328:817-20. Gottlieb AB, Chang GK Posnett DN, et al. Detection of transforming growth factor-o in normal, malignant, and hyperproliferative human keratinocytes. J Exp Med 1988; 167:670-5. Akhurst RJ, Fee F, Balmain A. Localized production of TGF-B mRNA in tumor promoter-stimulated mouse epidermis. Nature 1988;331:363-5. Ansel JC, Tiesman JP, Olerud JE, et al. Human keratinocytes are a major source of cutaneous platelet-derived growth factor. J Clin Invest 1993;92:671-8. Halaban R, Langdon R, Birchall N, et al. Basic fibroblast growth factor from human keratinocytes is a natural mitogen for melanocytes. J Cell Biol 1988;107:1611-9. Davies AM, Bandtlow C, Hermann R, et al. Timing and site of nerve growth factor synthesis in developing skin in relation to innervation and expression of the receptor. Nature 1987;326:353-8. Tron VA, Coughlin MD, Jang DE, et al. Expression and modulation of nerve growth factor in murine keratinocytes (PAM212). J Clin Invest 1990;85:1085-9. Kupper TS, Ballard DW, Chua AO, et al. Human keratinocytes contain mRNA indistinguishable from monocyte interleukin lo and B mRNA. J Exp Med 1986;164:2094100. Mizutani H, Black R, Kupper TS. Human keratinocytes produce but not process prointerleukin-1 (IL-l) beta. J Clin Invest 1991;87:1066-71. Anttila HSI, Reitamo S, Erkko P, et al. Membrane and cytosolic interleukin- 1 alpha and beta in normal human epidermal cells: variability of epitope exposure in immunohistochemistry. J Invest Dermatol 1990;95:31-8. Didierjean L, Groves RW, Saurat J-H. Interleukin-lol in normal skin. J Invest Dermatol 1991;96:294-5. Kupper TS, Min K, Sehgal P, et al. Production of IL-6 by ke-

Kondo and Saudev 797

85.

86.

87.

88. 89. 90. 91.

92.

93. 94. 95.

96.

97.

98.

99.

1100.

ratinocytes: implications for epidemial intlammation and immunity. Ann N Y Acad Sci 1989;557:454-65. Matsushima K, Morishita K, Yoshimura T, et al. Molecular cloning of a human monocyte-derived neutrophil chemotactic factor (MDNCF) and the induction of MDNCF mRNA by interleukin 1 and tumor necrosis factor. J Exp Med 1988; 167:1883-93. Kupper TS, Lee F, Birchall N, et al. Interleukin 1 binds to specific receptors on human keratinocytes and induces gmnulocyte macrophage colony-stimulating factor mRNA and protein: a potential autocrine role for interleukin-1 in epidermis. J Clin Invest 1988;82:1787-92. Heufler C, Koch F, Schuler G. Granulocyte/macrophage colony stimulating factor and interleukin 1 mediate the matnration of murine epidermal Langerhans cells into potent immunostimulatory dendritic cells. J Exp Med 1988;167:700-5. Steinman RM. Cytokines amplify the function of accessory cells. Immunol Lett 1988;17: 197-202. Koide SL, Inaba K, Steinman RM. Interleukin 1 enhances T dependent immune responses by amplifying the function of dendritic cells. J Exp Med 1987;165:515-30. Back 0, Linna J. In-vivo administration of interleukin 1 both enhances and suppresses contact sensitivity in mouse. Br J Dermatol 1992;126:125-30. Robertson B, Gahring L, Newton R, et al. In vivo administration of interleukin 1 to normal mice depress their capacity to elicit contact hypersensitivity responses: prostaglandins are involved in this modification of immune function. J Invest Dermatol 1987;88:380-7. Heufler C, Topar G, Koch F, et al. Cytokine gene expression in murine epidermal cell suspensions: interleukin 1B and macrophage inflammatory protein lo are selectively expressed in Langerhans cells but are differentially regulated in culture. J Exp Med 1992,176:1221-6. Enk AH, Katz SI. Early molecular events in the induction phase of contact sensitivity. Proc Natl Acad Sci U S A 1992; 89:1398-401. Enk AH, Angeloni VL, Udey MC, et al. An essential role for Langerhans cell-derived IL-l@ in the initiation of primary immune responses in skin. J Immunol 1993;150:3698-704. Grabbe S, Bmvers S, Granstein RD. Interleukin la but not transforming growth factor B inhibits tumor antigen presentation by epidermal antigen-presenting cells. J Invest Dermato1 1994;102:67-73. Dripps DJ, Brandhuber BJ, Thompson RC, et al. Interleukin 1 @L-l) receptor antagonist binds to the 80-kDa IL-1 receptor but does not initiate IL-1 signal transduction. J Biol Chem 1991;266:10331-6. Granowitz EV, Clark BD, Man&la J, et al. Interleukinl receptor antagonist competitively inhibits the binding of interlet&in-l to the type II interleukin-1 receptor. J Biol Chem 1991;266:14147-50. Dustin ML, Springer TA. Lymphocyte function-associated antigen-l @,FA-1) interaction with intercellular adhesion molecule-l (ICAM-1) is one of at least three mechanisms for lymphocyte adhesion to cultured endothelial cells. J Cell Biol 1988;107:321-31. Pober JS, Bevilacqua MP, Mendrick DL, et al. Two distinct monokines, interleukin 1 and tumor necrosis factor, each independently induce biosynthesis and transient expression of the same antigen on the surface of cultured human vascular endothelial cells. J Immunol 1986;136:1680-7. Dustin ML, Rothlein R, Bhan AK, et al. Induction by IL-1 and interferon-y. tissue distribution, biochemistry, and function of a natural adherence molecule (SCAM-1). J Immunol 1986;137:245-54.

Journal

798

Kondo and Sauder

101. Pober JS, Gimbrone MA, Lapierre LA, et al. Overlapping patterns of activation of human endothelial cells by interleukin-l, tumor necrosis factor, and immune interferon. J Jmmunol 1986;137:1893-6. 102. Osborn L, Hession C, Tizard R, et al. Direct expression cloning of vascular cell adhesion molecule 1, a cytokine-induced endothelial protein that binds to lymphocytes. Cell 1989; .59:1203-11. 103. Bevilacqua MP, Pober JS, Mendrick DL, et al. Identification of an inducible endothelial-leukocyte-adhesion-molecule. Proc Natl Acad Sci U S A 1987;84:9238-42. 104. Picker W, Treer JR, Ferguson-Darnell B, et al. Control of lymphocyte recirculation in man: I. differential regulation .of the peripheral lymph node homing receptor L-selection of T cells during the virgin to memory transition. J Immunol 1993;150:110.5-21. 105. Picker LJ, Treer JR, Ferguson-Dame11 B, et al. Control of lymphocyte recirculation in man: II. differential regulation of the cutaneous lymphocyte-associated antigen, a tissue-selective homing receptor for skin-homing T cells. J Immunol 1993;150:1122-36.

106. Picker LJ, Butcher EC. Physiological and molecular mechanisms of lymphocyte homing. Amru Rev Immunol 1992; 10:561-91. 107. Picker W, Kishimoto TK Smith CW, et al. ELAM-1 is an adhesion molecule for skin-homing T cells. Nature 1991; 349:796-g. 108. Groves RW, Allen MH, Barker JNWN, et al. Endothelial leukocyte adhesion molecule-l (ELAM-1) expression in cutaneous inflammation. Br J Dermatol 1991;124:117-23. 109. Shimizu Y, Shaw S, Graber N, et al. Activation-independent binding of human memory T cells to adhesion molecule ELAM-1. Nature 1991;349:799-802. 110. Koch F, Heufler C, Kipgen E, et al. Tumor necrosis factor alpha maintains the viability of murine epidermal Langerhans cells in culture, but in contrast to granulocyte/macrophage colony-stimulating factor, without inducing their functional maturation. J Exp Med 1990;171:150-71. 111. Cumberbatch M, Kimber I. Dermal tumor necrosis factor-a induces dendritic cell migration to draining lymph nodes;and possibly provides one stimulus for Langerhans cell migration. Immunology 1992;75:257-63. 112. Kurimoto I, Streilein JW. Cis-urocanic acid suppression of contact hypersensitivity induction is mediated via tumor necrosis factor 01.J Immunol 1992;148:3072-8. 113. Streilein JW. Sunlight and skin-associated lymphoid tissues (SALT): If UVB is the trigger and TNF alpha is its mediator, whatisthemessage? JInvest Dermatol1993;1OO(suppl):47S52s. 114. Kurimoto I, Streilein JW. Deleterious effects of cis-urocanic acid and UVB radiation on Langerhans cells and on induction of contact hypersensitivity are mediated by tumor necrosis factor-o. J Invest Dermatol 1992;99(suppl):69S-70s. 115. Simon JC, Edelbaun D, Bergstresser PR, et al. Distorted antigen-presenting function of Langerhans cells induced by tumor necrosis factor o( via a mechanism that appears different from that induced by ultraviolet B radiation. Photodennatol Photoimmunol Photomed 1991;8: 190-4. 116. Oxholm A, Oxholm P, Avnstorp C, et al. Keratinocyteexpression of interleukin-6 but not of tumor necrosis factoralpha is increased in the allergic and irritant patch test reaction. Acta Derm Venereol (Stockh) 1991;71:93-8. 117. Griffrths CE, Barker JNWN, Kunkel S, et al. Modulation of leukocyte adhesion molecules, a T cell chemotaxin (IL-8), and a regulatory cytokine (TNF-a) in allergic contact dermatitis (Rhus dermatitis). Br J Dermatol 1991$X519-26.

of the American

Academy

of Dermatology November 1995

118. Piguet PF, Grau GE, Hauser C, et al. Tumor necrosis factor is a critical mediator in hapten induced irritant and contact hypersensitivity reactions. J Exp Med 1991;173:673-9. 119. Bromberg JS, Chavin KD, Kunkel SL. Anti-tumor necrosis factor antibodies suppress cell-mediated immunity in vivo. J Immunol 1992;148:3412-7. 120. Jacob CO. Tumor necrosis factor 01in autoimmunity: Pretty girl or old witch? Immunol Today 1992;13:122-5. 121. Pober JS, Lapierre LA, Stolpen AH, et al. Activation of cultured human endothelial cells by recombinant lymphotoxin: comparison with tumor necrosis factor and interleukin 1 species. J Immunol 1987;138:3319-24. 122. Bevilacqua MP, Stengelin S, Gimbrone MA, et al. Endothelial leukocyte adhesion molecule 1: an inducible receptor for neutrophils related to complement regulatory proteins and lectins. Science 1989;243: 1160-5. 123. Sanders ME, Makgoba MW, Sharrow SO, et al. Human memory T lymphocytes express increased levels of three cell adhesion molecules (LFA-3, CD2, and LFA-1) and three other molecules (UCHL 1, CDw29, and Pgp- 1) and have enhanced lFN-7 production. J Immunol 1988;140:1401-7. 124. Tang A, Udey MC. Effects of ultraviolet radiation on murine epidermal Langerhans cells: doses of ultraviolet radiation that modulate ICAM- (CD54) expression and inhibit Langerhans cell function cause delayed cytotoxicity in vitro. J Invest ,Dermatol 1992;99:83-9. 125. Van Overveld FJ, Jorens PG, Rampart M, et al. Tumor necrosis factor stimulates human skin mast cells to release histamine and tryptase. Clin Exp Allergy 1991;21:71 l-4. 126. Pfeffer K, Matsuyama T, Kundig TM, et al. Mice deficient for the 55 kd tumor necrosis factor receptor are resistant to endotoxic shock, yet succumb to L. monocytogenes infection. Cell 1993;73:457-67. 127. Witmer-Pack MD, Olivier W, Valinsky J, et al. Granulocytemacrophage colony-stimulating factor is essential for the viability and function of cultnred murine epidermal Langerhans cells. J Exp Med 1987;166:1484-98. 128. Belsito DV, Epstein SP, Schultz JM, et al. Enhancement by various cytokines or 2-B-mercaptoethanol of Ia antigen expression on Langerhans cells in skin from normal aged and young mice. J Immunol 1989;143:1530-6. 129. Larsen CP, Ritchie SC, Hendrix R, et al. Regulation of immunostimulatory function and costimulatory molecule (B7-1 and B7-2) expression on murine dendritic cells. J Immunol 1994;152:5208-19. 130. Caux C, Dezutter-Dambuyant C, Schmitt D, et al. GM-CSF and TNF-or cooperate in the generation of dendritic Langerhans cells. Nature 1992;360:258-61. 13 1. Heir&h PC, Caste11JV, Andus T. Interleukin-6 and the acute phase response. Biochem J 1990;265:621-36. 132. Kimber I, Cumberbatch M, Humphreis M, et al. Contact hypersensitivity induces plasma interleukin 6. Int Arch Allergy Appl Immunol 1990;92:97-9. 133. I&ii T, Walsh LJ, Seymour GJ, et al. Modulation of Langerhans cell surface antigen expression by recombinant cytokine. J Oral Path01 Med 1990;19:355-9. 134. Katz AB, Taichman B. Epidermis as a secretory tissue: an in vitro tissue model to study keratinocyte secretion. J Invest Dermatol 1994;102:55-60. 135. Schreiber S, Kilgus 0, Payer E, et al. Cytokine pattern of Langerhans cells isolated from murine epidermal cell cultures. J Immunol 1992;149:352434. 136. Larrick J, Morhenn VB, Chiang YL, et al. Activated Langerham cells release tumor necrosis factor. J Leukoc Biol1989; 45:429-33. 137. Matsue H, Cruz PD Jr, Bergstresser PR, et al. Langerhans

Journal of the American Academy of Dermatology Volume 33, Number 5, Part 1

138.

139.

140. 141.

142. 143.

144.

145. 146.

147. 148.

149. 150.

151.

152.

153. 154.

155.

cells are the major source of mRNA for IL-1 B and MIP-la among unstimulated mouse epidermal cells. J Invest Dermato1 1992;99:537-41. Morhenn VB, Lee S, Euqui EM, et al. Human basal keratinocytes contain mRNA for IL-la and upon stimulation Langerhans cells express mRNA for IL-1 B [Abstract]. J In vest Dermatol 1989;92:485. Morhenn VB, Lee SW, Ilnicka M, et al. Activated human Langerhans cells express mRNA for IL-lo and IL-1B and produce these cytokines but do not secrete them. Cytokine 1992;4:500-5. Rothe MJ, Nowak M, Kerdel FA. The mast cell in health and disease. J AM ACAD DERMATOL 1990,23:615-24. Burd PR, Rogers HW, Gordon Jr, et al. Interleukin 3-dependent and -independent mast cells stimulated with IgE and antigen express multiple cytokines. J Exp Med 1989;170: 245-7. Plaut M, Pierce JH, Watson CJ, et al. Mast cell lines produce lymphokines in response to cross-linkage of Feel or to calcium ionophores. Nature 1989;339:64-7. Wodnar-Filipowicz A, Heusser C, Moroni C. Production of the haematopoietic growth factors GM-CSF and interleukin-3 by mast cells in response to IgE receptor-mediated activation. Nature 1989;339:150-2. Gordon JR, Galli SJ. Mast cells as a source of both preformed and newly synthesized tumor necrosis factor (Y (TNF-or)/ cache& by mouse mast cells stimulated via the FceRl: a mechanism for the sustained action of mast cell-derived TNF-(w during IgE-dependent biological responses. J Exp Med 1991;174:103-7. Pennington DW, Lopez AR, Thomas PS, et al. Dog mastocytoma cells produce transforming growth factor beta 1. J Clin Invest 1992;90:35-41. Casale TB, Wood D, Richerson HB, et al. Elevated bronchoalveolar lavage fluid histamine levels in allergic asthmatics are associated with methacholine bronchial hyperresponsiveness. J Clin Invest 1987;79:1197-203. Lam S, Chan H, Le Riche J, et al. Release of leukotrienes in patients with bronchial asthma. J Allergy Clin Immunol 1988;81:711-7. Camussi G, Aglietta M, Coda R, et al. Release of platelet activating factor and histamine: II. the cellular origin of human PAF: monocytes, polymorphonuclear neutrophils, and basohils. Immunology 1981;42:191-9. Paterson NAM, Wesserman SI, Said JW, et al. Release of chemical mediators from partially purified human lung mast cells. J Immunol 1976;117:1356-62. Klein LM, Lavker RM, Matis WL, et al. Degranulation of human mast cells induces an endothelial antigen central to leukocyte adhesion. Proc Natl Acad Sci U S A 1989; 86:8972-6. Walsh LJ, Trinchieri G, Waldorf HA, et al. Human dermal mast cells contain and release tumor necrosis factor-o. which induces endothelial leukocyte adhesion molecule-l. Proc Natl Acad Sci U S A 1991;88:4220-4. Askenase PW, Van Loveren H, Kraeuter-Kops S, et al. Defective elicitation of delayed-type hypersensitivity in W/WV and S1/Sld mast cell-deficient mice. J Immunol 1983; 131:2687-94. Galli SJ, Hammel I. Unequivocal delayed hypersensitivity in mast cell-deficient and beige mice. Science 1984;226:710-3. Kita H, Ohnishi T, Okubo Y, et al. Granulocyte/macrophage colony-stimulating factor and interleukin 3 release from human peripheral blood eosinophils and neutrophils. J Exp Med 1991;174:745-8. Wong DTW, Weller PF, Galli SJ, et al. Human eosinophils

Kondo and Sauder

156. 157. 158. 159. 160. 161. 162.

163. 164. 165. 166.

167. 168.

169.

170.

171. 172.

173.

174.

175. 176.

799

express transforming growth factor (Y. J Exp Med 1990; 172:673-81. Del Pozo V, De Andres B, Martin E, et al. Murine eosinophils and IL-l: IxIL-1 mRNA detection by in situ hybridization. J hnmunol 1990; 144:3 117-22. Hamid Q, Barkans J, Meng Q, et al. Human eosinophils synthesize and secrete interleukin-6, in vitro. Blood 1992; 80:1496-501. Galli SJ, Gordon JR, Wershil BK. Cytokine production by mast cells and basophils. Curr Gpin Immunol1991;3:865-73. Bos JD, Kapsenberg ML. The skin immune system: progress in cutaneous biology. Immunol Today 1993;14:75-8. Funk JO, Maibach HI. Horizons in pharmacologic intervention in allergic contact dermatitis. J AM ACAD DERMATOL 1994;31:999-1014. Femandez-Botran R. Soluble cytokine receptors: their role in immunoregulation. FASEB J 1991;5:2567-74. Kondo S, Kono T, Brown WR, et al. Lymphocyte functionassociated antigen- 1 (LFA- 1) is required for maximum elicitation of allergic contact dermatitis. Br J Dermatol 1994; 131:354-g. Arend WP. Interleukin 1 receptor antagonist: a new member of the interleukin 1 family. J Clin Invest 1991;8:1145-51. Debets R, Savelkoul HFJ. Cytokine antagonists and their potential therapeutic use. Immunol Today 1994;15:455-8. Dinarello CA, Thompson RC. Blocking IL-I: interleuldn 1 receptor antagonist in vivo and in vitro. Immunol Today 1991;12:404-10. Dripps DJ, Brandhuber BJ, Thompson RC, et al. Interleukin- 1 (IL- 1) receptor antagonist binds to the 80-kDa IL- 1 receptor but does not initiate IL-1 signal transduction. J Biol Chem 1991;266:20331-5. Fanslow WC, Sims JE, Sassenfeld H, et al. Regulation of alloreactivity in vivo by a soluble form of interleukin- 1 receptor. Science 1990;248:739-42. Alexander HR, Doherty GM, Buresch CM, et al. A recombinant human receptor antagonist to interleukin 1 improves survival after lethal endotoxemia in mice. J Exp Med 1991;173:1029-32. Cominelli F, Nast CC, Clark BD, et al. Interleukin 1 (IL-l) gene expression, synthesis, and effect of specific IL-1 receptor blockade in rabbit immune complex colitis. J Clin Invest 1990;86:972-80. Schwab JH, Anderle SK, Brown RR, et al. Pro- and anti-inflammatory roles of interleukin-1 in recurrence of bacterial cellwall-inducedarthritisinrats.Infecthnmun 1991;59:443642. Mullarkey MF, Leiferman KM, Peter MS, et al. Human cutaneous allergic late-phase response is inhibited by soluble IL-1 receptor. J Immunol 1994;152:2033-41. Ferretti M, Casini-Paggi V, Pizarro TT, et al. Neutralization of endogenous IL 1 receptor antagonist exacerbates and prolongs inflammation in rabbit immune colitis. J Clin Invest 1994;94:449-53. Lesslauer W, Tabuchi H, Gentz R, et al. Recombinant soluble tumor necrosis factor receptor proteins protect mice from lipopolysaccharide-induced lethality. Eur J Immunol 1991; 21:2883-6. Barton RW, Rothlein R, Ksiazek J, et al. The effect of anti-intercellular adhesion molecule-l on phorbol-ester-induced rabbit lung intlammation. J Immunol 1989;143: 127882. Isobe M, Yagita H, Okumura K, et al. Specific acceptance of cardiac allograft after treatment with antibodies to ICAMand LFA-1. Science 1992;255: 1125-7. Shiohara T, Moriya N, Gotoh C, et al. Locally administered

Journal

of the American

800 Kondo andSauder

177. 178. 179.

180.

18 1.

182. 183. 184.

185.

monoclonal antibodies to L3T4 prevent cutaneous gmft-vshost disease. J Immunol 1988;141:2261-7. Falanga PB, Butcher EC. Late treatment with anti-LFA-1 (CDlla) antibody prevents cerebral malaria in a mouse model. Eur J Immunol 1991;21:2259-63. Wahl SM, McCartney-Francis N, Mergenhagen G. Inflammatory and immunomodulatory roles of TGF-P. Immunol Today 1989;10:258-61. Keller J, Mantel C, Sing G, et al. Transforming growth factor p 1 selectively regulates early murine hematopoietic progenitors and inhibits the growth of IL-3-dependent myeloid leukemia cell lines. J Exp Med 1988;168:737-50. Epstein SP, Baer RL, Thorbecke GJ, et al. Immunosuppressive effects of transforming growth factor p: inhibition of the induction of Ia antigen on Langerhans cells by cytokines and of the contact hypersensitivity response. J Invest Dermatol 1991;96:832-7. Fiorentino DF, Bond MW, Mosmann TR. Two types of mouse T helper cell: IV. Th2 clones secrete a factor that inhibits cytokine production by Thl clones. J Exp Med 1989; 170:2081-95. Fiorentino DF, Zlotnik A, Vieira P, et al. IL-10 acts on the antigen presenting cell to inhibit cytokine production by Thl cells. J Immunol 1991;146:3444-51. Rousset F, Garcia E, Def&nce T, et al. IL-10 is a potent growth and differentiation factor for activated human I3 lymphocytes. Proc Nat1 Acad Sci U S A 1992;89:1890-3. Go NF, Cast01 BE, Barrett R, et al. Interleukin 10 (IL-lo), a novel B cell stimulatory factor: unresponsiveness of X chromosome-linked immunodeficiency B cells. J Exp Med 1990;172:162.5-31. Thompson-Snipes LA, Dhar V, Bond MW, et al. Interleukin 10: a novel stimulatory factor for mast cells and their progenitors. J Exp Med 1991;173:507-10.

AVAILABILITY

Academy

of Dermatology November 1995

186. Macatonia SE, Doherty TM, Knight SC, et al. Differential effect of IL-10 on dendritic cell-induced T cell proliferation and IFN--y production. J Immunol 1993;150:3755-65. 187. Fiorentino DF, Zlotnik A, Mosmann TR, et al. IL-10 inhibits cytokine production by activated macrophages. J Immunol 1991;147:3815-22. 188. De Waal Malefyt R, Abrams J, Bennett J, et al. Interleukin 10 (IL-lo) inhibits cytokine synthesis by human monocytes: an autoregulatory role of IL-10 produced by monocytes. J Exp Med 1991;174:1209-20. 189. De Waal Malefyt R, Haanen J, Spits H, et al. Interleukin 10 (IL-lo) and viral IL-10 strongly reduce antigen-specific human T cell proliferation by diminishing the antigen-presenting capacity of monocytes via downregulation of class Il major histocompatibility complex expression. J Exp Med 1991; 174:915-24. 190. Enk AH, Angeloni VL, Udey MC, et al. Inhibition of Langerhans cell antigen-presenting function by IL-lo. J Immunol 1993;151:2390-8. 191. Ferguson TA, Dube P, Griffith TS. Regulation of contact hypersensitivity by interleukin 10. J Exp Med 1994;179:1597604. 192. Enk AH, Saloga J, Becker D, et al. Induction of hapten-specific tolerance by interleukin 10 in vivo. J Exp Med 1994; 179:1392-402. 193. Schwarz A, Grabbe S, Riemann H, et al. In vivo effects of interleukin 10 on contact hypersensitivity and delayedtype hypersensitivity reactions. J Invest Dermatol 1994;103: 211-6. 194. Kondo S, McKenzie RC, Sauder DN. Interleukin-10 inhibits the elicitation phase of allergic contact hypersensitivity. J Invest Dermatol 1994,103:8 11-4.

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