Cytokine regulation of eosinophil function

CLINICAL

IMMUNOLOGY

AND

Vol. 62, No. 1, January,

IMMUNOPATHOLOGY

pp. S55-S59,1992

Cytokine

Regulation PETER

Division

of Infectious

Diseases,

Department

of Medicine,

Beth

of Eosinophil F. WELLER~ Israel

The development and function of eosinophils are regulated by a number of cytokines. Three cytokines have major effects on eosinophilopoiesis. Both granulocytemacrophage colony-stimulating factor (GM-CSF) and interleukin-3 stimulate the development of eosinophils as well as other leukocytes. Interleukind promotes eosinophil development and terminal differentiation. These three cytokines also effect the functions of mature eosinophils and can prolong their longevity in in vitro culture, enhance their capacity for release of leukotriene C, (LTC,), augment their capacity for helminthotoxicity and degranulation, and render them less dense (“hypodense”) than normal, unactivated eosinophils. GM-CSF can also induce the expression of HLA-DR on mature eosinophils, which can enable eosinophils to serve as antigen-presenting cells in stimulating T-cell responses.A T-cell-derived cytokine, lymphocyte chemoattractant factor (LCF), which stimulates the migration and function of CD4+ lymphocytes and eosinophils, also utilizes CD4 expressedon human eosinophils as its receptor. LCF stimulates eosinophil migration but not degranulation, leukotriene C, release, or respiratory burst activity. Interleukin-2 is also a potent chemoattractant for eosinophils. Thus, cytokines are involved in both increasedproduction of eosinophils as well as regulation of the functions of mature eosinophils. These functions of mature eosinophils include effector functions and collaborative interactions with lymphocytes and other tissue cellular elements. Q ISSZ Academic Press,

Function’**

Inc.

INTRODUCTION

Eosinophils throughout their life span, from their genesis within the bone marrow to their sites of functioning as mature cells within tissues, are subject to the stimulatory and regulatory effects of a number of cytokines. Undoubtedly, other cytokines, only recently identified or yet to be recognized, will also be found to effect eosinophil functioning. This paper considers ’ Presented as part of a symposium entitled “Future Directions of Cytokine and Immunoglobulin Therapy,” January ll-12,1991, Tucson, AZ. ‘Supported in part by grants (A120241, AI22571) from the National Institute of Allergy and Infectious Diseases. 3 To whom correspondence should be addressed at Beth Israel Hospital, Dana 617, 330 Brookline Avenue, Boston, Massachusetts 02215. s55

Hospital,

Harvard

Medical

School,

Boston,

Massachusetts

02215

some of the recognized effects of cytokines as contributing to eosinophilopoiesis and modulating the functions of mature eosinophils. These functions include not only effector functions of eosinophils, which are involved in helminthotoxicity and the immunopathogenesis of some eosinophil-related diseases, but also the collaborative functions which enable eosinophils to interact with and respond to lymphocytes and other immune cells as well as epithelial and mesenchymal cells. EFFECTS

ON EOSINOPHIL AND DIFFERENTIATION

DEVELOPMENT

Eosinophils develop within the bone marrow, and the regulation of eosinophilopoiesis has been known to be T-cell dependent since the classic studies of Beeson and Bass 0). At present, three cytokines are recognized to promote eosinophil development and differentiation. Both granulocyte-macrophage colonystimulating factor (GM-CSF) and interleukin-3 (IL-3) stimulate the development of eosinophils as well as other leukocytes, whereas IL-5 is specific in promoting the development and terminal differentiation of eosinophils (2, 3). The finding of heightened eosinophil production in transgenic mice expressing IL-5 suggests that IL-5 may also be sufficient to stimulate early stages in eosinophilopoiesis (4). In mice, IL-5 also promotes B-lymphocyte functions, including antibody production (51, although the effects of IL-5 on human B-cell functioning are less clear (6). IL-5, a product of the TH2 subset of lymphocytes in mice, is responsible for the eosinophilia that develops during experimental murine infections with helminthic parasites (7,8). In humans, increased levels of IL-5 have been detected in the serum or plasma of patients with eosinophilias of varying etiologies (9), including the idiopathic hypereosinophilic syndrome (101, parasitic infections (ll), and the tryptophan-induced eosinophilia-myalgia syndrome (12). T lymphocytes from patients with eosinophilia produce IL-5 after stimulation with IL-2 (13), and IL-5 production appears to mediate the eosinophilia that can develop during the therapeutic administration of IL-2 (14, 15). In Hodgkin’s disease of nodular sclerosis and mixed cellularity subtypes, which can be associated with eosinophilia, IL-5 mRNA transcripts have been detected

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within Reed-Sternberg cells ( 16). Eosinophilia may develop during therapeutic administration of GM-CSF (17, 18) but IL-5 appears to be the principal cytokine responsible for heightened eosinophilopoiesis. Conversely, interferon-a, which suppresses myelopoiesis, has been reported to be helpful in treating two patients with the idiopathic hypereosinophilic syndrome (19, 20). EFFECTS

ON

MATURE

EOSINOPHILS

As is true for other leukocytes, cytokines active in promoting growth and differentiation also effect functioning of the mature cells. The effects of cytokines on different classes of leukocytes are demonstrable in in vitro studies, but for human eosinophils there are indications that such effects do occur in uiuo. Over the years a number of morphologic, biochemical, and functional observations have been made that in the aggregate suggest that eosinophils from patients with heightened eosinophilia differ from those in normal individuals. ‘Activated”

Eosinophils

The diverse findings that indicate that eosinophils may be activated in uiuo and that “activated” eosinophils are present in the blood and tissues of patients with eosinophil-related diseases (21) include the following: (a) Morphologic alterations. These eosinophils may exhibit cytoplasmic vacuolization, alterations in granule numbers and size, and losses within specific granules of myelin basic protein-containing cores or matrix (22). (b) Diminished cell density. These eosinophils, when separated over density gradient media, are less dense (“hypodense”) than normal eosinophils. Hypodense eosinophils have been demonstrated in the blood of patients with asthma, helminthic infections, neoplasia, idiopathic hypereosinophilia, and other diseases associated with even mild eosinophilia (21, 231. (cl Increased surface receptors. These hypodense eosinophils may express more complement and IgG receptors (24). (d) Heightened parasite killing. The eosinophils from eosinophilic donors exhibit greater cytotoxicity in parasite killing assays (25). (e) Increased metabolic activity. The eosinophils from eosinophilic donors are metabolically more active with increased hexose monophosphate shunt activity, glucose uptake, and superoxide anion generation (26, 27). (f> Enhanced leukotriene C4 (LTC,) generation. These eosinophils form more LTC, in response to submaximal concentrations of the calcium ionophore A23187 and other stimuli (23). (g> Prolonged survival. Eosinophilic donor-derived

eosmophils live ionger wtthout cytokme ~oppirrnt*nl,: tion during zn vitro cuhure. These alterations in various properties o: eoslnoph il% provide evidence that eosinophils had been subjected I.&: activating stimuli zn I-~UJand they have been observe~.i with cells circulating in the blood of eosinophilic p:: tients with diverse diseases. Whether the stirnull ii,% and the nature of activation are the same ir .I?1 d !‘~ eases, and by what mechanisms the stimuli acr are noi yet clear; but the process of activation, whether it. b!, occurring in part systemically or principally localized within tissue sites, results in the appearance wither: the bloodstream of functionally activated eosinophils. Eosinophil Effector Functions Some features of apparently activated blood eosinophils, such as their diminished densities, might reflect populations of less mature eosinophils entering the blood in diseases with accelerated eosinophilopoiesis, but the findings that specific cytokines convert normal mature eosinophils into those expressing attributes of activated eosinophils indicated that parameters of activation reflected not immaturity but rather effects of stimulation. Mature eosinophils have receptors for IL5, IL-3, and GM-CSF (28-30). Each of these three cytokines with eosinophilopoietic activity, IL-5, IL-3 and GM-CSF, can activate eosinophils in vitro, prolong their survival in culture, render them hypodense, and enhance their capacities for LTC, generation and their helminthotoxic activities (31-34). In addition IL-5 and GM-CSF enhance Ig receptor-induced eosinophil degranulation (35). IL-5 is a chemoattractant for eosinophils (36). Thus, mature eosinophils are responsive to stimulation by the same cytokines that are involved ;n stimulating intramedullary eosinophil formation and the effector functions of mature eosinophils can be enhanced by cytokine activation. IL-5, like IL-3 and GMCSF, can likewise enhance histamine release and LTC, release from basophils (37, 38). Other cytokines, including an eosinophil cytotoxicity-enhancing factor (391, and interferon--y (40) and agents, including platelet-activating factor (411, also activate eosinophil effector functions. Because eosinophils normally are predominantly tissue-dwelling cells and function in tissue sites, where greater eosinophil infiltration and accumulation may be elicited in association with specific disease processes, the capacity of eosinophils to respond to cytokines elaborated by cells within tissues is pertinent to the local regulation of eosinophil functioning within tissue domains. That mesenchymal cells elaborate substances active on eosinophils is exemplified by the findings that eosinophil survival is enhanced when eosinophils are cultured with human fibroblasts, human or bovine endothelial cells, or fibroblast and endothelial cell-conditioned media (42-44). In the presence of IL-5,

CYTOKINES

AND

IL-3, and GM-CSF, mesenchymal cells (both fibroblasts and endothelial cells) can promote eosinophil survival and augment eosinophil effector functions (3133). Mesenchymal cells, such as fibroblasts, can elaborate cytokines (45) and cytokines derived from these cells, like such T-cell-derived cytokines as IL-5, may regulate the functioning of eosinophils within normal and inflamed tissue sites. COLLABORATIVE

FUNCTIONS

OF

EOSINOPHILS

In addition to the effector responses of eosinophils, which include heightened oxygen radical and eicosanoid formation, degranulation, and toxicity for cells and parasite targets, it is being appreciated that eosinophils have other functional capabilities. Thus, mature eosinophils may engage in both effector responses of end-stage cells and collaborative interactions with lymphocytes and other cell types. Mature eosinophils, neither those derived from the blood of normal donors nor those phenotypically activated eosinophils from the blood of eosinophilic donors, express major histocompatibility complex (MHC) class II proteins like HLA-DR (46). When mature bloodderived eosinophils are maintained in culture with murine 3T3 fibroblasts and GM-CSF, they are induced to synthesize and express HLA-DR (46). Thus, not only are mature eosinophils capable of protein synthesis, in contrast to some older beliefs that held that mature eosinophils had lost such capacity with differentiation, but also eosinophils can express a protein that would be necessary for them to serve as antigen-presenting cells in stimulating T-lymphocyte responses. Cytokines, notably GM-CSF, are necessary for such induction of eosinophil HLA-DR expression. More recently, eosinophils induced to express HLA-DR have been shown to function as antigen-presenting cells capable of eliciting antigen-specific responses in T cells (47). Eosinophils, both normal and eosinophilic donorderived blood cells, express CD4 and synthesize this transmembrane protein when eosinophils are maintained in culture with 3T3 fibroblasts and GM-CSF (48). The expression of CD4 by human eosinophils enables eosinophils, like CD4+ lymphocytes and CD4+ monocytes, to respond to a novel lymphokine, lymphocyte chemoattractant factor (LCF). LCF on both lymphocytes and monocytes utilizes CD4 as its receptor and stimulates responses, including enhanced migration and HLA-DR expression (49-51). LCF, elaboration of which can be elicited by specific antigen and by histamine, is a potent chemoattractant for human eosinophils (52). LCF does not directly stimulate or prime for enhanced degranulation, LTC!, release, or oxygen radical generation (52). Eosinophils also respond to IL-2 with enhanced migration (53). Thus, both IL-2 and LCF are lymphocyte-derived cytokines, like IL-5, capable of enhancing eosinophil responses.

s57

EOSINOPHILS

As exemplified by the recent documentation that eosinophils can elaborate the cytokine transforming growth factor-a (TGF-a) (54, 551, eosinophils themselves may be sources of cytokines capable of effecting the functions of mesenchymal, epithelial, and immune cells. The finding that eosinophil expression of TGF-a was not uniform among human blood and tissue eosinophils suggests that eosinophil cytokine expression may be regulated by other cytokines effecting eosinophils (55). CONCLUSIONS

Cytokines are intimately involved in regulating not only the production of eosinophils but also the functions of mature eosinophils. Cytokines which enhance the effector responses of eosinophils include those active during eosinophilopoiesis, GM-CSF, IL-3, and IL5. In addition to their functions as end-stage effector cells, eosinophils have other functional abilities and as such are akin to macrophages. Eosinophils can stimulate lymphocytes, even serving as antigen-presenting cells, and can elaborate cytokines capable of effecting functions of other cells present within tissues in conjunction with eosinophils. Various cytokines are being identified which stimulate these collaborative functional capabilities of eosinophils. REFERENCES 1. Beeson, P. B., and Bass, D. A., “The Eosinophil,” Saunders, Philadelphia, 19’77. 2. Clutterbuck, E. J., Hirst, E. M., and Sanderson, C. J., Human interleukin-5 (IL-51 regulates the production of eosinophils in human bone marrow cultures: Comparison and interaction with IL-l, IL-3, IL-6, and GM-CSF. Blood 73, 1504-1512, 1989. 3. Sonoda, Y., Arai, N., and Ogawa, M., Humoral regulation of eosinophilopoiesis in vitro: Analysis of the targets of interleukin-3, granulocyte/macrophage colony-stimulating factor (GMCSF), and interleukin-5. Leukemia 3, 14-18, 1989. 4. Dent, L. A., Strath, M., Eosinophilia in transgenic Exp. Med. 172, 1425-1431, 5. Mizel,

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Received July 26, 1991; accepted September 23, 1991

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