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Regulation of immune and inflammatory responses by interleukin 1
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Vol. 3, No. 18
September 21, 1982
Regulation of Immune and Inflammatory Responses by Interleukin 1 Steven B. Mizel, Ph.D. Microbiology Program Pennsylvania State University University Park, Pennsylvania 16802 The macrophage is an essential participant in the initiation and amplification of immune and inflammatory responses. Underlying the functional reactivity of the macrophage is its rather unique ability to interact with and regulate the behavior of a diverse group of cell types, including T and B lymphocytes, fibroblasts, synovial cells, chondrocytes, and hepatocytes, that are involved in the development and propagation of immune and inflammatory responses. The accumulated evidence indicates that the communication link between these cell populations and the macrophage is mediated in large part by a single peptide mediator termed interleukin 1 (IL-I). Early Studies In 1972, Gery et al. (8) reported that stimulated human and murine macrophages produce a factor termed lymphocyte-activating factor (LAF) that is mitogenic for murine thymocytes. LAF also possesses the ability to synergize with suboptimal concentrations of T-cell mitogens such as phytohemagglutinin (PHA) and concanavalin A (conA) in the induction of thymocyte proliferation. In addition to the thymocyte mitogenie activity described by Gery and colleagues, macrophages have been found to produce an activity
that is capable of restoring the in vitro antibody responses of spleen cells that are T-lymphocyte-depleted (23). Wood et al. (23) suggested that the macrophage-derived mediator was acting directly on the antibodyproducing B cell, and thus they termed this factor B-cell-activating factor (BAF). Between 1976 and 1979, the relationship between the macrophage-derived activities responsible for thymocyte proliferation and the augmentation of in vitro antibody responses was rather unclear and thus was a subject of considerable controversy. However, in view of the results obtained in the biochemical characterization of these macrophage products (13, 17), it was evident that a single peptide or family of peptides was involved in the macrophage stimulation of T-cell proliferation and antibody synthesis. This mediator, interleukin 1, is considered to be synonymous with LAF and BAF (1, 15). Purification and Chemical Characterization of IL-1 One of the major problems in the field of lymphokine research has been the inability to obtain large amounts of a mediator from normal macrophages or lymphocytes. Fortunately, a number of tumor cell lines of lymphocyte and macrophage origin have recently been characterized in terms of their ability to produce relatively large amounts of lymphokines. Indeed, murine IL-1 has recently been purified to homogeneity (16) by using as start-
ing material culture fluid from a murine macrophage cell line, P388D,. IL-1 from both human and murine macrophages appears to be composed of a single peptide chain of molecular weight 15,000 (16). Human IL-I exhibits isoelectric points of approximately 5, 6, and 7, whereas murine II-I possesses pI values of 4.7 and 4.9. It is not clear as to whether there is any biologic significance to the charge heterogeneity of IL-1. The purified IL-I is extremely potent, being active in the 10-1tM-to-10-1°M range. Studies are now in progress to define the amino acid sequence of murine IL-1. Biologic Actions of IL-1 on Lymphocytes The role of IL-1 in T-celldependent immune responses is well established. IL-1 is involved not only in the proliferation of T ceils but also in the generation of helper (12) and cytotoxic T cells (6). Although In This Issue lnterleukin 1 . . . . . . . . . . . . . . . . . . 123 An hnportant regulator o f hmnune and inflammatory responses Guest Editorial . . . . . . . . . . . . . . . . 126 1L-l: Its role hi disease and possible future applications Letter to the Editor . . . . . . . . . . . . 128 Pitfalls in the immunofluorescent technique for the detection of imnnmoglobulin on B cells Future Meetings . . . . . . . . . . . . . . .
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IL-I is an antigen-nonspecific mediator, it functions as an essential activating signal in all T-celldependent, antigen-specific immune responses, the specificity of a given response being defined by the eliciting antigen (2, 6). Underlying the stimulatory effects of IL-I is its participation in the induction of interleuken 2 (IL-2), the T-cell-derived lymphokine that is ultimately responsible for the proliferation of T cells (9). This link between IL-I and IL-2 is an essential element in the T-cell-activation sequence because it involves the conversion of a primary macrophage-derived maturational signal into a secondary T-cell-derived proliferative signal that results in the amplification of specific immune responses. The stimulation of IL-2 synthesis by IL-1 is dependent upon the presence of another activating signal, either a specific antigen or a polyclonal T-cell mitogen, such as PHA or conA. This requirement for a second signal in IL-2 induction may explain the general dependence of IL-1 on the presence of a secondary signal for the enhancement of a variety of immune responses. An important component of IL-1 activity is its ability to regulate a variety of cell-surface receptors that are involved in lymphocyte maturation or functional activation (e.g., Thy 1, Lyt, and stable (37 °C) E-rosette receptors on T cells; and Ia, surface immunoglobulin, and complement receptors on bone marrow B-cell precursor cells). Human T lymphocytes possess the capacity to form rosettes (E-rosettes) with red blood cells from a number of species. The majority of human T cells form E-rosettes at 4°C. These rosettes readily dissociate, however, when the temperature is raised from 4 ° to 37 °C. In certain disease states, human peripheral blood T cells develop the capacity to form E-rosettes that are stable at 37 °C. For example, in some patients with acute lymphatic leukemia, a relatively high proportion of the leukemic cells form stable E-rosettes (3). A
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similar increase in stable E-rosetteforming activity has been observed with the T cells from patients with chronic active hepatitis (5) or rheumatoid arthritis (7). T-cell stimulants such as conA (20) stimulate an increase in the number of stable E-rosette-forming T cells. These findings have led to the proposal that the appearance of the stable E-rosette receptor site may be a reflection of T-cell activation. Of considerable interest is the observation that IL-1 can markedly stimulate the generation of stable E-rosette-forming human peripheral blood T cells (2). Within 24 hours after addition of IL-I, the percentage of stable E-rosette positive cells increases from 2°/0 to 60°'/0; this plateau value is equal to that seen in a number of disease states (e.g., rheumatoid arthritis) (7). These findings raise the interesting possibility that elevated levels of IL-1 may be partly responsible for the enhanced generation of activated, stable E-rosette-forming T cells in certain disease states. The results of studies by Hoffman et al. (10) indicate that IL-I may also participate in the regulation of the phenotype of bone marrow B-cell precursors. IL-l-treated bone marrow cells were found to exhibit a relatively rapid (within 2.5 hr) increase in the expression of three B-cell surface markers, Ia, surface immunoglobulin, and complement receptors. No increase in the T-cell marker, Thy 1, was detected. Hoffman has postulated that IL-1 induces the differentiation of B cells and thus increases the frequency of B cells that are capable of responding to helper T cells. Thus it appears that IL-1, in concert with a specific antigen, stimulates the clonal expansion of specific helper or cytotoxic T cells. This effect is mediated by the induction of IL-2, a lymphokine that is directly mitogenic for T cells. IL-I may also contribute to immunoresponsiveness by enhancing the maturation of both T cells and B cells.
Biologic Effects of IL-1 on NonLymphoid Cells Evidence from a number of studies indicates that IL-1 has a spectrum of biologic activities that includes effects on non-lymphoid as well as lymphoid cells. Although the observations on the effects of IL-1 on non-lymphoid cells were initially rather surprising, it is clear that the modulation of non-lymphoid cell functions by IL-1 is consistent with the known role of macrophages in the regulation of a variety of cell types (including fibroblasts, chondrocytes, and synovial cells) that participate in inflammatory responses. Isolated human adherent synovial cells obtained from rheumatoid synovectomy preparations in primary culture produce large quantities of collagenase and prostaglandins (4). The in vivo production of collagenase and prostaglandins by these synovial cells may contribute to some of the pathologic events in the joints of patients with rheumatoid arthritis. In vitro, rheumatoid synovial cells exhibit a time-dependent decrease in the ability to produce collagenase and prostaglandins (4). Production of these substances can be restored, however, by the addition of culture supernatant from peripheral blood mononuclear cells. Recently, we found that purified IL-1 possesses the ability to markedly stimulate synovial cell collagenase and prostaglandin production (14). Analysis of the T lymphocytes in synovial fluid from patients with rheumatoid arthritis indicates that these cells are activated in terms of proliferation, stable E-rosette-forming capacity, and macrophage-activating activity (7). In view of the ability of IL-1 to initiate T-cell proliferation and the generation of stable E-rosette-forming human peripheral blood T cells (2), it is quite possible that macrophages in the synovium, through their elaboration of a single mediator, IL-1, may regulate the inflammatory activity of both T cells and synovial cells. In view of the
Clinical Immunology Newsletter
stimulatory effect of antigenantibody complexes or Fc fragments on IL-1 production, it is quite possible that high levels of immune complexes may contribute to a sustained stimulation o f IL-I production, thereby enhancing tissue destruction and inflammation in rheumatoid arthritis and perhaps in other chronic inflammatory diseases. Fibroblasts may be another important cell target of IL-1. Human dermal fibroblast proliferation is enhanced in a concentrationdependent manner by IL-1 (21). Fibrosis is a common occurrence in a number of chronic inflammatory diseases, such as rheumatoid arthritis, scleroderma, disseminated lupus erythematosus, and silicosis. IL-1 may contribute to the excessive collagen deposition observed in such diseases by stimulating a localized increase in the population o f fibroblasts capable of producing collagen. Future in vivo experiments with IL-1 and monoclonal antibodies against IL-1 should permit us to analyze the possible effects of IL-1 on collagen degradation (due to stimulation of collagenase synthesis) as opposed to collagen synthesis and deposition in acute and chronic inflammatory responses. Are these two opposing processes separated temporally by differences in their IL-1 concentration-dependence? Fever occurs in varying degrees in most instances o f acute inflammation and in many cases in which the local tissue reaction is chronic in nature. Recent evidence (18) clearly indicates that the macrophage is the only source of the endogenous pyrogen (also termed leukocytic pyrogen and leukocyte endogenous mediator) that may mediate the great majority o f fevers. Recent studies by Rosenwasser and Dinarello (19) and Murphy et al. (18) indicate that endogenous pyrogen and IL-1 activities may reside in the same peptides. Thus it appears that IL-I can modulate the functional activity of another nonlymphoid cell type. In this particular case, the IL-1 target cell may be located in or near the central her-
Copyright © 1982 by G. K. Hall & Co.
vous system control center for temperature regulation, the anterior hypothalamus. Kampschmidt (11) has found that the leukocytie endogenous mediator enhances the in vivo release o f a number o f acute-phase reactant proteins, including fibrinogen, haptoglobin, a, and az macrofetoprotein, ceruloplasmin, and C-reactive protein. More recently, Stzein et al. (22) have demonstrated that IL-1 stimulates the in vivo release of serum amyloid A, a major component of the amyloid A fibrils that accumulate during the development o f amyloidosis secondary to chronic inflammation. It is quite likely that the hepatocyte is the primary cell target o f IL-1 in the induction o f acute-phase reactants. Thus it appears that the macrophage, via a single peptide mediator, IL-1, may regulate the behavior of a variety of cells that are involved in acute and chronic inflammatory responses. IL-1 may participate in the activation of infiltrating lymphocytes and of cells involved in the destruction or deposition of connective tissue as well as in fever production. Sufficient evidence is now available to conclude that IL-1 is the major activating signal of the macrophage in immune and inflammatory responses.
Conclusions The rate of progress in the study o f interleukin 1 biology and biochemistry has been especially rapid during the last few years. Although IL-I was initially described as a thymocyte mitogenic factor, it is now clear that a broader biologic definition is required. IL-1 appears to be the macrophagederived mediator that is essential for the initiation and amplification of all T-cell-dependent immune responses. In addition, IL-1 appears to participate in the inflammatory response as an inducer of inflammatory mediators (14), acute-phase reactants (11, 22), and fever (18, 19). Thus IL-1 may permit the macrophage to regulate in a con-
certed fashion the in vivo behavior o f a variety o f cell types that are involved in immune and inflammatory responses. In many respects, it may be of value to consider this fascinating molecule not only as a monokine but also as a true hormone. Although IL-1 may be a second signal for a number of adjuvants, it may prove quite difficult to uze IL-1 for therapeutic purposes since this mediator has such a broad spectrum o f effects (e.g., fever induction and stimulation o f collagenase and prostaglandin production by non-lymphoid cells, in addition to lymphocyte activation). It may be more appropriate to consider strategies to diminish endogenous in vivo IL-I activity. For example, given the possible role of IL-1 in the pathology o f rheumatoid arthritis and, presumably, other inflammatory diseases, it may be of considerable value to use monoclonal antibodies or antibody fragments directed against IL-1 or its receptor site(s) to titrate the activity of IL-I to a lower, more normal level. Alternatively, fragments o f IL-1 may be isolated that bind but do not stimulate target cells. It now seems rather evident that the in vivo regulation o f IL-1 activity in various immune and inflammatory diseases will have profound therapeutic implications.
References 1. Aarden, L. A., et al. 1979. Letter to the editor. Revised nomenclature for antigen--nonspecific T cell proliferation and helper factors. J. Immunol. 123:2928-2929. 2. Ben-Zvi, A., S. B. Mizel, and J. J. Oppenheim. 1981. Generation of human peripheral blood stable E-rosette-forming T cells by interleukin 1. Clin. Immunol. Immunopathol. 19:330-337. 3. Borella, L., and L. Sen. 1974. E-receptors on blasts from untreated acute lymphocytic leukemia (ALL): Comparison of temperature dependence of E-rosettes formed by normal and leukemic lymphoid cells. J. Immunol. 114:187-193. 4. Dayer, J. M., et al. 1979. Participation of monocyte-macrophages and lymphocytes in the production of a factor that stimulates collagenase
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and prostaglandin. J. Clin. Invest. 64:1386-1392. Eliakim, M., el al. 1975. Lymphocyte subpopulations in chronic active hepatitis: Increase in lymphocytes forming stable E-rosettes. Ciin. Immunol. Immunopathol. 4:538-544. Farrar, W. L., S. B. Mizel, and J. J. Farrar. 1980. Participation of lymphocyte activating factor (interleukin 1) in the induction of cytotoxic T cell responses. J. Immunol. 124:1371-1377. Galili, U., et al. 1979. Activated T cells in the synovial fluid of arthritic patients: Characterization and comparison with in vitro activated human and murine T cells in cooperation with monocytes in cytotoxicity. J. Immunol. 122:878-883. Gery, I., R. K. Gershon, and B. H. Waksman. 1972. Potentiation of the T-lymphocyte response to mitogens. I. The responding cell. J. Exp. Med. 136:128-142. Giilis, S., M. Scheid, and J. Watson. 1980. Biochemical and biologic characterization of lymphocyte regulatory molecules. III. The isolation and phenotypic characterization of interleukin 2 producing T cell lymphomas. J. Immunol. 125:2570-2578. Hoffman, M. K., et al. 1979. Macrophage factor controlling differentiation of B ceils. J. Immunol. 122:497-502. Kampschmidl, R. F. 1980.
12.
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Biological manifestations of leukocytic endogenous mediator, pp. 150-153. In D. Schlessinger (ed.), Microbiology 1980. American Society for Microbiology, Washington, D.C. Koopman, W. J., J. J. Farrar, and J. Fuller-Bonar. 1978. Evidence for the identification of lymphocyte activating factor as the adherent cellderived mediator responsible for enhanced antibody synthesis by nude mouse spleen cells. Cell Immunol. 35:92-98. Mizel, S. B. 1979. Physicochemical characterization of lymphocyte activating factor (LAF). J. Immunol. 122:2167-2172. Mizel, S. B., et al. 1981. Stimulation of rheumatoid synovial cell collagenase and prostaglandin production by partially purified lymphocyte activating factor (interleukin 1). Proc. Natl. Acad. Sci. USA 78:2474-2477. Mizel, S. B., and A. Ben-Zvi. 1980. Studies on the role of lymphocyte activating factor (interleukin I) in antigen-induced lymph node lymphocyte proliferation. Cell. Immunol. 54:382-389. Mizel, S. B., and D. Mizel. 1981. Purification to apparent homogeneity of murine interleukin I. J. Immunol. 126:834-837. Mizel, S. B., J. J. Oppenheim, and D. L. Rosenstreieh. 1978. Characterization of lymphocyteactivating factor (LAF) produced by the macrophage cell line, P388D,.
18.
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21. 22.
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II. Biochemical characterization of LAF induced by activated T cells and LPS. J. Immunol. 120:1504-1508. Murphy, P. A., P. L. Simon, and W. F. Willoughby. 1980. Endogenous pyrogens made by rabbit peritoneal exudate cells are identical with lymphocyte activating factors made by rabbit alveolar macrophages. J. Immunol. 124:2498-2501. Rosenwasser, L. J., and C. A. Dinarello. 1981. Ability of human leukocytic pyrogen to enhance phytohemagglutinin induced murine thymocyte proliferation. Ceil. Immunol. 63:134-142. Schlesinger, M., and T. Kertes. 1979. The formation of stable E-rosettes by human peripheral blood Iymphocytes after short exposure to concanavalin A. Clin. Immunol. Immunopathol. 12:1-11. Schmidt, J. A., et al. 1982. ILl, a potential regulator of fibroblast proliferation. J. Immunol. In press. Stzein, M. B., et al. 1981. The role of macrophages in the acute-phase response: SAA inducer is closely related to lymphocyte-activating factor and endogenous pyrogen. Cell. Immunol. 63:164-176. Wood, D. D., and S. L. Gaul. 1974. Enhancement of the humoral response of T cell-depleted murine spleens by a factor derived from human monocytes in vitro. J. Immunol. 113:925-933.
Guest Editorial T h e R e l a t i o n o f I n i e r l e u k e n 1 to Other Mediators Stanley Cohen, M.D. Professor of Pathology The University o f Connecticut Health Center Farmington, Connecticut 06032 In this issue, Dr. Steven Mizel reviews the physical and biologic properties of interleukin 1 (IL-1, LAF). This macrophage-derived factor can synergize mitogen-induced T-cell proliferation and can influence antibody responses in T-celldepleted systems. At least some of its effects are due to its ability to serve as a cofactor in the induction o f lymphocyte-derived growth fac-
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tors. Interleukin 1 is but one o f a wide variety of macrophage-derived factors (monokines) that exert important biologic effects on other cells. As Mizel indicated, macrophage products can influence fibroblasts and parenchymal cells. In addition, it has been shown that they can provide chemotactic signals for other i n f l a m m a t o r y cells (3). Macrophages can produce colony stimulatory factor (5) and procoagulants (7). They can also suppress lymphocyte proliferative responses and lymphokine production, possibly by mechanisms involving prostaglandins (9). The ability of macrophages to serve as accessory cells for mediator production by T
cells is probably not due to IL-1, since in this situation intact cells or cell m e m b r a n e preparations, rather than soluble factors, are required (8). As attempts to purify IL-1 and other m a c r o p h a g e and lymphocyte products grow increasingly successful, we will be able to more precisely associate specific biologic effects with specific macromolecules and demonstrate their identity or lack of identity. One excellent example, cited by Mizel, is the surprising discovery that IL-1 m a y be identical to endogenous pyrogen. The observation that non-macrophage lines can produce IL-1 (4) and our own observation that non-lymphoid cells
Clinical ImmunologyNewsletter
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Vol. 3, No. 18
September 21, 1982
Regulation of Immune and Inflammatory Responses by Interleukin 1 Steven B. Mizel, Ph.D. Microbiology Program Pennsylvania State University University Park, Pennsylvania 16802 The macrophage is an essential participant in the initiation and amplification of immune and inflammatory responses. Underlying the functional reactivity of the macrophage is its rather unique ability to interact with and regulate the behavior of a diverse group of cell types, including T and B lymphocytes, fibroblasts, synovial cells, chondrocytes, and hepatocytes, that are involved in the development and propagation of immune and inflammatory responses. The accumulated evidence indicates that the communication link between these cell populations and the macrophage is mediated in large part by a single peptide mediator termed interleukin 1 (IL-I). Early Studies In 1972, Gery et al. (8) reported that stimulated human and murine macrophages produce a factor termed lymphocyte-activating factor (LAF) that is mitogenic for murine thymocytes. LAF also possesses the ability to synergize with suboptimal concentrations of T-cell mitogens such as phytohemagglutinin (PHA) and concanavalin A (conA) in the induction of thymocyte proliferation. In addition to the thymocyte mitogenie activity described by Gery and colleagues, macrophages have been found to produce an activity
that is capable of restoring the in vitro antibody responses of spleen cells that are T-lymphocyte-depleted (23). Wood et al. (23) suggested that the macrophage-derived mediator was acting directly on the antibodyproducing B cell, and thus they termed this factor B-cell-activating factor (BAF). Between 1976 and 1979, the relationship between the macrophage-derived activities responsible for thymocyte proliferation and the augmentation of in vitro antibody responses was rather unclear and thus was a subject of considerable controversy. However, in view of the results obtained in the biochemical characterization of these macrophage products (13, 17), it was evident that a single peptide or family of peptides was involved in the macrophage stimulation of T-cell proliferation and antibody synthesis. This mediator, interleukin 1, is considered to be synonymous with LAF and BAF (1, 15). Purification and Chemical Characterization of IL-1 One of the major problems in the field of lymphokine research has been the inability to obtain large amounts of a mediator from normal macrophages or lymphocytes. Fortunately, a number of tumor cell lines of lymphocyte and macrophage origin have recently been characterized in terms of their ability to produce relatively large amounts of lymphokines. Indeed, murine IL-1 has recently been purified to homogeneity (16) by using as start-
ing material culture fluid from a murine macrophage cell line, P388D,. IL-1 from both human and murine macrophages appears to be composed of a single peptide chain of molecular weight 15,000 (16). Human IL-I exhibits isoelectric points of approximately 5, 6, and 7, whereas murine II-I possesses pI values of 4.7 and 4.9. It is not clear as to whether there is any biologic significance to the charge heterogeneity of IL-1. The purified IL-I is extremely potent, being active in the 10-1tM-to-10-1°M range. Studies are now in progress to define the amino acid sequence of murine IL-1. Biologic Actions of IL-1 on Lymphocytes The role of IL-1 in T-celldependent immune responses is well established. IL-1 is involved not only in the proliferation of T ceils but also in the generation of helper (12) and cytotoxic T cells (6). Although In This Issue lnterleukin 1 . . . . . . . . . . . . . . . . . . 123 An hnportant regulator o f hmnune and inflammatory responses Guest Editorial . . . . . . . . . . . . . . . . 126 1L-l: Its role hi disease and possible future applications Letter to the Editor . . . . . . . . . . . . 128 Pitfalls in the immunofluorescent technique for the detection of imnnmoglobulin on B cells Future Meetings . . . . . . . . . . . . . . .
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IL-I is an antigen-nonspecific mediator, it functions as an essential activating signal in all T-celldependent, antigen-specific immune responses, the specificity of a given response being defined by the eliciting antigen (2, 6). Underlying the stimulatory effects of IL-I is its participation in the induction of interleuken 2 (IL-2), the T-cell-derived lymphokine that is ultimately responsible for the proliferation of T cells (9). This link between IL-I and IL-2 is an essential element in the T-cell-activation sequence because it involves the conversion of a primary macrophage-derived maturational signal into a secondary T-cell-derived proliferative signal that results in the amplification of specific immune responses. The stimulation of IL-2 synthesis by IL-1 is dependent upon the presence of another activating signal, either a specific antigen or a polyclonal T-cell mitogen, such as PHA or conA. This requirement for a second signal in IL-2 induction may explain the general dependence of IL-1 on the presence of a secondary signal for the enhancement of a variety of immune responses. An important component of IL-1 activity is its ability to regulate a variety of cell-surface receptors that are involved in lymphocyte maturation or functional activation (e.g., Thy 1, Lyt, and stable (37 °C) E-rosette receptors on T cells; and Ia, surface immunoglobulin, and complement receptors on bone marrow B-cell precursor cells). Human T lymphocytes possess the capacity to form rosettes (E-rosettes) with red blood cells from a number of species. The majority of human T cells form E-rosettes at 4°C. These rosettes readily dissociate, however, when the temperature is raised from 4 ° to 37 °C. In certain disease states, human peripheral blood T cells develop the capacity to form E-rosettes that are stable at 37 °C. For example, in some patients with acute lymphatic leukemia, a relatively high proportion of the leukemic cells form stable E-rosettes (3). A
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similar increase in stable E-rosetteforming activity has been observed with the T cells from patients with chronic active hepatitis (5) or rheumatoid arthritis (7). T-cell stimulants such as conA (20) stimulate an increase in the number of stable E-rosette-forming T cells. These findings have led to the proposal that the appearance of the stable E-rosette receptor site may be a reflection of T-cell activation. Of considerable interest is the observation that IL-1 can markedly stimulate the generation of stable E-rosette-forming human peripheral blood T cells (2). Within 24 hours after addition of IL-I, the percentage of stable E-rosette positive cells increases from 2°/0 to 60°'/0; this plateau value is equal to that seen in a number of disease states (e.g., rheumatoid arthritis) (7). These findings raise the interesting possibility that elevated levels of IL-1 may be partly responsible for the enhanced generation of activated, stable E-rosette-forming T cells in certain disease states. The results of studies by Hoffman et al. (10) indicate that IL-I may also participate in the regulation of the phenotype of bone marrow B-cell precursors. IL-l-treated bone marrow cells were found to exhibit a relatively rapid (within 2.5 hr) increase in the expression of three B-cell surface markers, Ia, surface immunoglobulin, and complement receptors. No increase in the T-cell marker, Thy 1, was detected. Hoffman has postulated that IL-1 induces the differentiation of B cells and thus increases the frequency of B cells that are capable of responding to helper T cells. Thus it appears that IL-1, in concert with a specific antigen, stimulates the clonal expansion of specific helper or cytotoxic T cells. This effect is mediated by the induction of IL-2, a lymphokine that is directly mitogenic for T cells. IL-I may also contribute to immunoresponsiveness by enhancing the maturation of both T cells and B cells.
Biologic Effects of IL-1 on NonLymphoid Cells Evidence from a number of studies indicates that IL-1 has a spectrum of biologic activities that includes effects on non-lymphoid as well as lymphoid cells. Although the observations on the effects of IL-1 on non-lymphoid cells were initially rather surprising, it is clear that the modulation of non-lymphoid cell functions by IL-1 is consistent with the known role of macrophages in the regulation of a variety of cell types (including fibroblasts, chondrocytes, and synovial cells) that participate in inflammatory responses. Isolated human adherent synovial cells obtained from rheumatoid synovectomy preparations in primary culture produce large quantities of collagenase and prostaglandins (4). The in vivo production of collagenase and prostaglandins by these synovial cells may contribute to some of the pathologic events in the joints of patients with rheumatoid arthritis. In vitro, rheumatoid synovial cells exhibit a time-dependent decrease in the ability to produce collagenase and prostaglandins (4). Production of these substances can be restored, however, by the addition of culture supernatant from peripheral blood mononuclear cells. Recently, we found that purified IL-1 possesses the ability to markedly stimulate synovial cell collagenase and prostaglandin production (14). Analysis of the T lymphocytes in synovial fluid from patients with rheumatoid arthritis indicates that these cells are activated in terms of proliferation, stable E-rosette-forming capacity, and macrophage-activating activity (7). In view of the ability of IL-1 to initiate T-cell proliferation and the generation of stable E-rosette-forming human peripheral blood T cells (2), it is quite possible that macrophages in the synovium, through their elaboration of a single mediator, IL-1, may regulate the inflammatory activity of both T cells and synovial cells. In view of the
Clinical Immunology Newsletter
stimulatory effect of antigenantibody complexes or Fc fragments on IL-1 production, it is quite possible that high levels of immune complexes may contribute to a sustained stimulation o f IL-I production, thereby enhancing tissue destruction and inflammation in rheumatoid arthritis and perhaps in other chronic inflammatory diseases. Fibroblasts may be another important cell target of IL-1. Human dermal fibroblast proliferation is enhanced in a concentrationdependent manner by IL-1 (21). Fibrosis is a common occurrence in a number of chronic inflammatory diseases, such as rheumatoid arthritis, scleroderma, disseminated lupus erythematosus, and silicosis. IL-1 may contribute to the excessive collagen deposition observed in such diseases by stimulating a localized increase in the population o f fibroblasts capable of producing collagen. Future in vivo experiments with IL-1 and monoclonal antibodies against IL-1 should permit us to analyze the possible effects of IL-1 on collagen degradation (due to stimulation of collagenase synthesis) as opposed to collagen synthesis and deposition in acute and chronic inflammatory responses. Are these two opposing processes separated temporally by differences in their IL-1 concentration-dependence? Fever occurs in varying degrees in most instances o f acute inflammation and in many cases in which the local tissue reaction is chronic in nature. Recent evidence (18) clearly indicates that the macrophage is the only source of the endogenous pyrogen (also termed leukocytic pyrogen and leukocyte endogenous mediator) that may mediate the great majority o f fevers. Recent studies by Rosenwasser and Dinarello (19) and Murphy et al. (18) indicate that endogenous pyrogen and IL-1 activities may reside in the same peptides. Thus it appears that IL-I can modulate the functional activity of another nonlymphoid cell type. In this particular case, the IL-1 target cell may be located in or near the central her-
Copyright © 1982 by G. K. Hall & Co.
vous system control center for temperature regulation, the anterior hypothalamus. Kampschmidt (11) has found that the leukocytie endogenous mediator enhances the in vivo release o f a number o f acute-phase reactant proteins, including fibrinogen, haptoglobin, a, and az macrofetoprotein, ceruloplasmin, and C-reactive protein. More recently, Stzein et al. (22) have demonstrated that IL-1 stimulates the in vivo release of serum amyloid A, a major component of the amyloid A fibrils that accumulate during the development o f amyloidosis secondary to chronic inflammation. It is quite likely that the hepatocyte is the primary cell target o f IL-1 in the induction o f acute-phase reactants. Thus it appears that the macrophage, via a single peptide mediator, IL-1, may regulate the behavior of a variety of cells that are involved in acute and chronic inflammatory responses. IL-1 may participate in the activation of infiltrating lymphocytes and of cells involved in the destruction or deposition of connective tissue as well as in fever production. Sufficient evidence is now available to conclude that IL-1 is the major activating signal of the macrophage in immune and inflammatory responses.
Conclusions The rate of progress in the study o f interleukin 1 biology and biochemistry has been especially rapid during the last few years. Although IL-I was initially described as a thymocyte mitogenic factor, it is now clear that a broader biologic definition is required. IL-1 appears to be the macrophagederived mediator that is essential for the initiation and amplification of all T-cell-dependent immune responses. In addition, IL-1 appears to participate in the inflammatory response as an inducer of inflammatory mediators (14), acute-phase reactants (11, 22), and fever (18, 19). Thus IL-1 may permit the macrophage to regulate in a con-
certed fashion the in vivo behavior o f a variety o f cell types that are involved in immune and inflammatory responses. In many respects, it may be of value to consider this fascinating molecule not only as a monokine but also as a true hormone. Although IL-1 may be a second signal for a number of adjuvants, it may prove quite difficult to uze IL-1 for therapeutic purposes since this mediator has such a broad spectrum o f effects (e.g., fever induction and stimulation o f collagenase and prostaglandin production by non-lymphoid cells, in addition to lymphocyte activation). It may be more appropriate to consider strategies to diminish endogenous in vivo IL-I activity. For example, given the possible role of IL-1 in the pathology o f rheumatoid arthritis and, presumably, other inflammatory diseases, it may be of considerable value to use monoclonal antibodies or antibody fragments directed against IL-1 or its receptor site(s) to titrate the activity of IL-I to a lower, more normal level. Alternatively, fragments o f IL-1 may be isolated that bind but do not stimulate target cells. It now seems rather evident that the in vivo regulation o f IL-1 activity in various immune and inflammatory diseases will have profound therapeutic implications.
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Guest Editorial T h e R e l a t i o n o f I n i e r l e u k e n 1 to Other Mediators Stanley Cohen, M.D. Professor of Pathology The University o f Connecticut Health Center Farmington, Connecticut 06032 In this issue, Dr. Steven Mizel reviews the physical and biologic properties of interleukin 1 (IL-1, LAF). This macrophage-derived factor can synergize mitogen-induced T-cell proliferation and can influence antibody responses in T-celldepleted systems. At least some of its effects are due to its ability to serve as a cofactor in the induction o f lymphocyte-derived growth fac-
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tors. Interleukin 1 is but one o f a wide variety of macrophage-derived factors (monokines) that exert important biologic effects on other cells. As Mizel indicated, macrophage products can influence fibroblasts and parenchymal cells. In addition, it has been shown that they can provide chemotactic signals for other i n f l a m m a t o r y cells (3). Macrophages can produce colony stimulatory factor (5) and procoagulants (7). They can also suppress lymphocyte proliferative responses and lymphokine production, possibly by mechanisms involving prostaglandins (9). The ability of macrophages to serve as accessory cells for mediator production by T
cells is probably not due to IL-1, since in this situation intact cells or cell m e m b r a n e preparations, rather than soluble factors, are required (8). As attempts to purify IL-1 and other m a c r o p h a g e and lymphocyte products grow increasingly successful, we will be able to more precisely associate specific biologic effects with specific macromolecules and demonstrate their identity or lack of identity. One excellent example, cited by Mizel, is the surprising discovery that IL-1 m a y be identical to endogenous pyrogen. The observation that non-macrophage lines can produce IL-1 (4) and our own observation that non-lymphoid cells
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