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Biological properties of interleukin 10 Maureen Howard and Anne O'Garra

An enormous amount of information on interleukin 10 (IL-IO) has been gathered since its original description as cytokine synthesis inhibition factor (CSIF) several years ago. In this short article, Maureen Howard and Anne

Interleukin 10 (IL-10) (Refs 1-3) O'Garra summarize what is currently IL-10-mediated suppression of cyto- is an acid-sensitive protein of known of the biological properties of kine synthesis also occurs when 35-40 kDa that is produced under IL-IO and speculate on its clinical either TH1 T-cell clones a6 or natural different conditions of immune acti- potential, killer (NK) cells 17 are activated by vation by the TH0 and TH2 subsets IL-2 and accessory cells in an of helper T cells 1,3, as well as by antigen-nonspecific, MHC-unrestric- monocytes, macrophages and B ted manner. This inhibition is also cells 4-6. IL-10 was initially dis- cytokine production 1,3 and antigen- via an indirect action of IL-10 on the covered I and isolated2, 3 on the basis specific proliferation TM of cultured macrophage/monocyte population, of its ability to suppress cytokine clones of TH1 cells when they are suggesting modulation of other synthesis by Ti-tl helper T cells, activated in an accessory cell- effector mechanisms critical for While genomic analysis clearly con- dependent manner. Furthermore, in macrophage/monocyte accessory firms the mammalian origin of this some in vitro systems, the addition cell function. cytokine 2,7, IL-10 displays remark- of anti-IL-10 antibodies to primary While these additional macro- able homology to a previously un- cultures of helper T cells enhances phage/monocyte accessory cell effec- characterized open reading frame, the emergence of cells bearing a Trtl- tor mechanisms have not yet been termed BCRF1, in the Epstein-Barr cell phenotype is. Collectively, these elucidated, numerous other effects virus (EBV) genome2,3, 8. The protein data suggest that IL-10 may play a of IL-10 on cultured macrophage/ encoded by BCRF1 (now designated role in diminishing delayed-type hy- monocytes have been defined. In vlL-10) exhibits partial IL-10 ac- persensitivity reactions and other the absence of any notable effect tivity 8, suggesting that EBV may Tial cell-mediated responses. The on the expression of a variety have captured this mammalian gene inhibition of TH1 cell development of macrophage/monocyte adhesion to confer some survival advantage and function is due to an indirect molecules 4, IL-10 nevertheless onitself.Theavailabilityofrecombi- action of IL-10 on a subpopulation causes a profound change in the nant mouse 2 and human 3 IL-10, to- of accessory cells rather than a morphology and adhesion of per- getherwithneutralizingmonoclonal direct action on the TH1 cells itoneal macrophages s or cultured antibodies that recognize these themselves 1,14,16. monocytes (R. de Waal Malefyt, proteins specifically 4,9, has allowed IL-10 suppresses the ability of unpublished). IL-10 also inhibits identification of an array of murine macrophages, but not B cells, the production by macrophage/ immunosuppressive and immuno- to stimulate THl-cell clones to monocytes of numerous inflamma- stimulatory properties associated synthesize cytokines 16. Similarly, tory mediators, including IL-lo~, with this cytokine, human monocyte- or mouse macro- IL-6, IL-8, granulocyte-macrophage

phage-dependent proliferation of colony-stimulating factor (GM- Immunosuppressive properties of TH1 cells is also inhibited by CSF), granulocyte colony-stimu- IL-10 in vitro IL-10, while TH1 cell proliferation lating factor (G-CSF) and TNF-

The helper T-cell compartment of induced by transformed human od,s, TM. In addition, endogenous IL-10 the immune system contains nu- B-cell lines 14 or murine dendritic suppresses synthesis of IL-10 by merous subpopulations that are cells (S. Macatonia and A. O'Garra, macrophages/monocytes 4, suggest- distinguishable on the basis of unpublished) is not. ing negative feedback regulation differential cytokine production It is likely that this suppression of monocyte-derived IL-10 pro- profiles (reviewed in Refs 10,11). of monocyte/macrophage antigen- duction. IL-10 also suppresses the One such subpopulation, the T,1 presenting cell function is due, in production of reactive nitrogen subset, is characterized by pro- part, to the demonstrated ability of oxides 18,19, intracellular metabolites duction of gamma-interferon IL-10 to strongly downregulate con- that are involved in the elimination (IFN-y), IL-2, tumour necrosis fac- stitutive and inducible expression of of intra- and extracellular parasites. tor [3 (TNF-~3), but not IL-4, IL-5, MHC class II molecules on human Importantly, IL-10 does not com- IL-10 (Ref. 10), and appears to me- monocytes (HLA-DR/DP and DQ) TM pletely suppress all monocyte/ diate delayed-type hypersensitivity and on murine peritoneal exudate macrophage protein synthesis, since reactions in some in vivo situ- macrophages (M. Stein and S. it has no effect on the constitutive ations 12,13. IL-10 suppresses both Gordon, pers. commun.). However, expression of transforming growth

© 1992, Elsewer Science Publishers Ltd, UK.

Immunology Today 198 rot. 13 No. 6 1992

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factor 13 (TGF-~) 4 and it upregulates ated from concanavalin A-activated IL-10-treated mice exhibit a mark- expression of the IL-1 receptor CD8 ÷ splenic T cells 26, and mark- edly increased susceptibility to antagonist (IL-lra) (R. de Waal edly expands the clone size and lytic death by lipopolysaccharide (LPS)- Malefyt et al., unpublished), an potential of these cells when assayed induced shock (H. Ishida and M. important regulator of inflamma- against appropriate target cells 26. Howard, unpublished), an inflam- tory reactions. IL-10 is also a stimulant of murine matory reaction resulting from

mast cells, synergizing with IL-3 and elevation of numerous monokines Immunostimulatory properties of IL-4 to induce proliferation of sev- (reviewed in Ref. 29). These ad- IL-10 in vitro eral murine mast cell lines 27. Perhaps ditional modifications may also rep-

While IL-10 is a potent immuno- more significantly, IL-10 markedly resent a secondary consequence of suppressant of macrophage func- enhances the total number and aver- IFN-~ elevation 29,3~. tion, it exerts a wide array of im- age size of mast cell colonies which Additional insights into the func- munostimulatory effects on B cells, develop from mesenteric lymph tions of IL-10 in vivo have come These include enhancement of in node cellsofnematode-infectedmice from numerous studies exploring vitro viability and upregulation of after 14 days culture in the presence mouse models of parasitic infec- MHC class II molecule expression of IL-3 and IL-4 (Ref. 27). tions. These have demonstrated that by highly purified, small, dense B IL-10 is produced during certain cells obtained from the spleens of Action of mouse IL-10 in vivo parasitic infections 32,33 and that it unstimulated mice 2°. Interestingly, The physiological role of IL-10 inhibits both IFN-~/production and B cells from X-linked immune de- has been studied in a series of ex- macrophageeffector function 19'34'3s. ficient (xicl) mice are incapable of periments in mice in which IL-10 Since Tiql cells mediate protective upregulating MHC class II ex- function was blocked by continu- immunity in the particular parasitic pression in response to IL-10 stimu- ous administration of neutralizing infections used in these studies, the lation 2°, despite the apparent monoclonal antibodies 28,29. Mice data suggest a regulatory role for existence of functional IL-10 recep- treated continuously from birth until IL-10 in the mediation of suscep- tors on these cells, and the upregu- 8 weeks of age with anti-IL-10 anti- tibility to acute disease in these lation of class II expression in re- bodies seem to be essentially healthy models. sponse to IL-4 stimulation (N. Go and, by numerous parameters, un- and M. Howard, unpublished). This changed; however, a series of highly Potential clinical applications of currently unexplained observation reproducible phenotypic changes IL-10 raises the possibility that IL-10 con- have been observed. One fundamen- The striking biological properties tributes to the immunodeficiency of tal modification that may account described above justify some specu- xid mice, which are unresponsive to for all of the other phenotypic lation regarding the possible clinical thymus-independent type II antigens changes is the elevation of endogen- uses of IL-10. The ability of IL-10 in B-cell bioassays in vitro, and are ous IFN-~/ levels 28,29, an outcome to suppress the production of inflam- susceptible to an array of microorga- that is clearly consistent with the matory monokines while at the nisms in vivo 2t. ability of IL-10 to suppress pro- same time upregulating the anti-

In terms of effects on activated duction of this cytokine by TH0, T,1 inflammatory agent IL-lra, suggests Bcells, IL-l O augments both their pro- and NK cells in vitro. For reasons that it may be a potent anti- liferation and differentiation into not yet understood, this elevation of inflammatory reagent in a variety of antibody-secreting cells. This has endogenous IFN-~/results in a selec- clinical situations, for example bac- been demonstrated most convinc- tive depletion of a numerically minor terial sepsis, rheumatoid arthritis ingly using human B cells, stimu- subpopulationofBcells(reviewedin and psoriasis. Indeed, preliminary lated either via the Ig receptors or by Ref. 30), designated as Ly-1, CD5 or animal model experiments have in- the combination of anti-CD40 anti- B-1 B cells. The depletion of Ly-1 B dicated that IL-10 can effectively bodies and IL-4. In these systems, cells in mice treated with anti-IL-10 protect mice from death resulting IL-10 augments DNA synthesis and is indicated by striking reductions from LPS-induced shock (M. expansion of the activated B cells, (1) in the number of peritoneal- Howard and S. Menon, unpublished and induces their differentiation resident B cells, (2) in circulating data). The ability of IL-10 to sup- into antibody-producing cells that IgM and IgA antibody levels, and press a subset of T-cell-derived secrete large amounts of IgM, IgG (3) in specific antibody responses to cytokines (e.g. TFN-y, IL-2, TNF-f3), and lgAantibodies 22,23. two bacterial antigens, phosphoryl- in addition to monokine sup-

In addition to its effects on B cells, choline and oL1,3 dextran 28,29, a corn- pression, makes it an attractive can- IL-10 is a stimulant of numerous bination of properties attributable didate for prolonging allograft other cell types. It augments the in to the Ly-1 B-cell subpopulation survival, and in treating a variety of vitro proliferative response of (reviewed in Refs 29,30). In addition T-cell-mediated autoimmune dis- murine thymocytes and T cells that to a depletion of Ly-1 B cells, anti- eases, such as type 1 diabetes and have been activated with IL-2 and IL-10-treated mice are also charac- multiple sclerosis. IL-4 24'2s and may, therefore, play a terized by elevated serum levels of In other clinical situations, antag- role in T-cell development. In single- IgG2a, IgG2b, and, in some cases, onism of IL-10 may be more desir- cell cultures containing IL-2, IL-10 IL-6 (Ref. 29). The latter is probably able. The expression of IL-10 increases the frequency of murine indicative of a more generalized up- activity (vlL-10) by EBVpresumably cytotoxic T-cell precursors gener- regulation of monokines, since anti- confers some survival advantage to

Immunology Today 199 vol 13 No. 6 1992

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the virus, so IL-10 antagonists may 17 Hsu, D-H., Moore, K.W. and Spits, 26 Chen, W-F. and Zlotnik, A. (1990) boost antiviral immunity to EBV and H. Int. Immunol. (in press) J. Immunol. 147, 528-534 possibly other viruses. Similarly, 18 Bogdan, C., Vodovotz, Y. and 27 Thompson-Snipes, L., Dhar, V., IL-10 antagonists may provide effec- Nathan, C. (1991) J. Exp. Med. 174, Bond, M.W. et al. (1991) J. Exp. Med. tive therapy in infectious diseases 1549-1555 173,507-510 19 Gazzinelli, R.T., Oswald, I.P., 28 Ishida, H., Hastings, R., Kearney, J. where IL-10 has been shown to in- James, S.L. et al. J. Immunol. (in press) et al. J. Exp. Med. (in press) bibit macrophage-mediated immun- 20 Go, N.F., Castle, B.E., Barrett, R. 29 Howard, M., O'Garra, A., Ishida, ity against intra- and extracellular et al. (1990) J. Exp. Med. 172, H. et al. J. Clin. Immunol. (in press) parasites. Thus, the properties of this 1625-1631 30 Herzenberg, L.A., Stall, A.M., cytokine suggest that IL-10 or IL-10 21 Scher, I. (1982) Adv. Immunol. 33, Lalor, P.A. et al. (1986) Immunol. Rev. antagonists may be efficacious in 1-71 93, 81-102 diminishing the clinical pathology 22 Rousset, F., Garcia, E., Defrance, T. 31 Snapper, C.M. and Paul, W.E. associated with a diverse set of et al. Proc. NatIAcad. Sci. USA (1987) Science 236, 944-947 diseases. (in press) 32 Minoprio, P. NY Acad. Sci.

23 Defrance, T., Vanbervliet, B., (in press)

Maureen Howard and Anne O'Garra Bri~re,175,671-682F" et al. (1992) J. Exp. Med. 33S.S. Heinzel,et al. (1991)F'P" Proc.Sadick'NatlM'D"Acad.MUtha'sci.

are at D N A X Research Institute, 901 24 Suda, T., O'Garra, A., MacNeil, I. USA 88, 7011-7015 California Avenue, Palo Alto, CA et al. (1990) Cell. Immunol. 129, 34 Silva, J.S., Morrissey, P.J., 94304-1104, USA. 228-240 Grabstein, K.H. et al. (1992)]. Exp.

25 MacNeil, I., Suda, T., Moore, K.W. Med. 175,169-174 et al. (1990) J. Immunol. 145, 35 Sher, A., Fiorentino, D., Caspar, P.

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and Gallagher, R.B., eds), pp. R eviews A58-A61, Elsevier Trends Journals • • • 13 Badaro, R., Falcott, E., Badaro, F.S. et al. (1990) New Engl. J. Med. 322, * ~ ~ ' " " e , T u m o u r - ; n ~ l t r a t ; n ' ~ ~ w - .l'rmnhocvtes: 16-21 14 de Waal Malefyt, R., Haanen, J., angels or devils ~ Yssel, H. et al. (1991) J. Exp. Med. 174, 915-924 * Antagonists of lipopolysaccharide 15 Hsieh, C-S., Heimberger, A.B., Gold, J.S. et al. Proc. Natl Acad. Sci. * Molecular aspects of human T-cell USA (in press) 16 Fiorentino, D.F., Zlotnik, A., deficiency Vieira, P. et al. (1991) J. Immunol. 146, 3444-3451

Immunology Today 200 vot 13 No. 6 1992