Trends in Molecular Medicine

Immunosuppressive and Anti-inflammatory Properties of lnterleukin 10

Jan E. de Vries

lnterleukin 10 (11-1 0) indirectly prevents antigen-specific T-cell activation, which is associated with downregulation of the antigen presentation and accessory cell functions of monocytes, macrophages, Langerhans cells and dendritic cells. In addition, 11-10 inhibits T-cell expansion by directly inhibiting 11-2 production by these cells. These properties of 11-10, together with its capacity to downregulate the production of pro- inflammatory cytokines and chemokines by activated monocytes, polymorphonuclear leucocytes and eosinophils, indicate that 11-10 is a potent immunosuppressant in vitro. 11-1 0 has similar activities in vivo. It inhibits lipopolysaccharide or staphylococcal enterotoxin 6 induced lethal shock in mice. In addition, 11-10 deficient mice develop chronic inflammatory bowel disease, which could be reduced, or prevented by 11-10 treatment. 11-10 also prevented the development of colitis in a SClD mouse model.

Collectively, these data indicate that 11-10 has great potential therapeutical utility in the treatment of diseases, such as chronic inflammation, autoimmune diseases, transplant rejection, graft-versus-host disease and sepsis.

Key words: 11-10; immunosuppression; inflammatory bowel disease.

(Annals of Medicine 27: 537-541, 1995)

Introduction

Immune responses are regulated by complex direct interactions between cells of the immune system and cytokines secreted by these cells following activation. T lymphocytes and monocytes are important producers of cytokines. CD4' T-helper cells, both in mice and man, can be divided into at least three major subpopulations, based on their cytokine production profiles (1). Human T-helper 1 (Thl) cells secrete, among other cytokines, IL-2 and interferon 7 (IFN-;I) but no IL-4 or IL-5, whereas Th2 cells produce generally high levels of IL-4 and IL-5 but no, or very low, levels of IFN-;,. A third T-helper subset, Tho cells, produce both Thl and Th2 cytokines. The differences in cytokine production patterns of the various T-cell subsets is reflected in the functions of these cells: Thl cells are predominantly involved in cellular immune responses, such as delayed

From the Department of Human Immunology, DNAX Research Institute of Molecular and Cellular Biology, Palo Alto, CA, USA.

Address and reprint requests: J. E. de Vries, PhD, Department of Human Immunology, DNAX Research Institute of Molecular and Cellular Biology, 901 California Avenue, Palo Alto, CA 94304-1 104, USA.

anti-inflammatory effects; lethal shock;

hypersensitivity reactions, whereas Th2 cells are superior in providing help to 6 cells in antibody production. More recently, it has become clear that imbalances between Thl and Th2 responses are associated with many diseases, including infectious diseases, chronic inflammation, autoimmune diseases and allergy (reviewed in (2)).

The cytokine IL-10 was described initially as a murine Th2 cell product, which inhibited cytokine synthesis by Thl cells (3). More recent studies however, have shown that human IL-10 (hlL-10) is not a typical Th2 cell cytokine, as it is also produced by CD4 + Tho and Thl cells, CD8' T cells, 6 cells, monocytes/ macrophages, keratinocytes and various tumour cell lines, including B- cell lymphomas, certain melanomas, ovarian and colon carcinomas (4-10). Human IL-10 is a protein consisting of 160 amino acids with a predicted molecular size of 18.5 kD and it exists as a homodimer with a molecular size of 37 kD (11). Like all cytokines, IL-10 is pleiotropic. It modulates the functions of many immunocompetent cells, including T, 6, natural killer (NK) cells, monocytesl macrophages and neutrophils (for recent reviews see (10, 12, 13)).

In the present review, the major immunosuppressive and anti-inflammatory effects of human (h) IL-10 in vitro and mouse IL-10 in vivo, will be summarized briefly. In

Ann Med 27

Ann

Med

Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

Uni

vers

itaet

s- u

nd L

ande

sbib

lioth

ek D

uess

eldo

rf o

n 08

/28/

13Fo

r pe

rson

al u

se o

nly.

538 de Vries

addition, the potential clinical use of hlL-10 will be discussed.

11-1 0 Prevents Antigen-specific T-cell Proliferation

Antigen induced T-cell activation involves engagement of the T-cell receptor (TCR) by an antigenic peptide- class II MHC complex. In addition, costimulatory signals provided by interactions between CD28, expressed on T cells, with its ligands CD80 or CD86 present on antigen- presenting cells (APC), such as monocytes, dendritic cells, B cells or Langerhans cells, are required for optimal T-cell proliferation (14, 15). However, before these interactions can occur T-cell-APC contacts have to be established through interactions between adhesion molecules, such as LFA-1 and CD2 with their ligands CAM-1 and LFA-3 expressed on T cells and APC, respectively (16, 17). Activation of the T cells results in the induction of IL-2 production and IL-2 receptor expression. Interactions of IL-2 with the IL-2 receptor induce in T-cell proliferation.

Recent in vitro studies have shown that hlL-10 strongly inhibits the antigen-specific proliferative responses of peripheral blood T cells and CD4' T- helper cells belonging to the Tho, Thl or Th2 subset (5). IL-10 also strongly inhibited the proliferation of alloreactive T cells in mixed lymphocyte reactions and of alloreactive T-cell clones in response to stimulation with allogeneic monocytes, dendritic cells or Langerhans cells (1 8-20). This inhibition of antigen- induced T-cell proliferation by IL-10 is, for the major part, mediated indirectly by inhibition of the antigen- presenting capacity of the APC, because monocytes pretreated with IL-10, failed to induce antigen-specific T- cell proliferation (5). These results, which indicate that IL-10 actually prevents T-cell activation, are consistent with the observation that antigen-presentation by monocytes pretreated with IL-10 failed to raise the intracellular Ca2 ' concentrations in the responding T cells (5). The mechanisms by which IL-10 inhibits antigen-specific T-cell expansion are still ill defined, but the fact that IL-10 downregulates many of the molecules on APC, which are essential for T-cell activation, probably contributes to the inhibition of Ag-presenting capacity of these cells. Prevention of antigen-specific T- cell activation by IL-10 was found to be associated with a strong downregulation of class II MHC molecules on the surface of APCs, such as human monocytes, dendritic cells and Langerhans cells (5, 18-20). IL-10 also downregulates constitutive and IFN-;l-induced expression of the adhesion molecule CAM-1 (CD54) and of CD80 and CD86, which are the ligands for the T- cell costimulatory molecule CD28 (21 -24). Interactions between CD86 or CD80 with CD28 are important for initiating the activation of resting T cells, and for enhancing T-cell activation and T-cell expansion, respectively (1 4, 15). Downregulation of CD86 and CD80 expression on APCs by IL-10 would, therefore, strongly interfere with these processes.

In addition to these indirect inhibitory effects on T-cell activation via APCs, IL-10 has direct inhibitory effects on antigen-induced T-cell proliferation (25). IL-10 directly inhibits proliferation of T cells activated by anti-CD3 mAbs in the absence of APC. This inhibition of proliferation occurs through inhibition of IL-2 production by the T cells at the transcriptional level. IL-10 also directly inhibits TNF-a production by activated T cells, whereas IL-4, IL-5, IFN-y and GM-CSF production was not affected significantly (25). Thus, IL-10 inhibits T-cell proliferation in two ways; indirectly, by inhibiting the antigen-presenting capacity and accessory cell function of APC, as well as directly, through downregulation of IL-2 gene expression in the responding T cells.

11-10 Inhibits the Production of Proinflammatory Cytokines and Chemokines by Monocytes and

Neutrophils

Activation of human monocytes results in the production of proinflammatory cytokines, which not only include IL- la , IL-lp, IL-6, tumour necrosis factor r (TNF-x), but also chemokines such as IL-8 and MIP-lr (24, 26, 27). Proinflammatory cytokines and chemokines play a major role in the activation of neutrophils, monocytesl macrophages, NK cells, T cell and B cells and in the recruitment of these cells to sites of inflammation (28).

IL-10 strongly inhibits the production of these pro- inflammatory cytokines and chemokines (24, 26, 27). In addition to its inhibitory effects on proinflammatory cytokines and chemokines, IL-10 inhibits the production of granulocyte-macrophage colony stimulating factor (GM-CSF) and granulocyte (G)-CSF by activated monocytes (24, 26, 27). Despite the primary function of GM- and G-CSF being to promote the growth of early haematopoietic progenitor cells, these cytokines can activate monocyte/macrophages and neutrophils and enhance the production of proinflammatory cytokines by these cells, which implies that they have a strong proinflammatory component.

IL-10 has comparable effects on the production of proinflammatory cytokines and chemokines by activated human polymorphonuclear leucocytes (PMN) and eosinophils (29-32). However, IL-10 does not have general inhibitory effects of cytokine production by monocytes and neutrophils because it induces, for example, the production of the IL-1 receptor antagonist (IL-1 ra), a cytokine which binds with high affinity to type I and type I I IL-1 receptors without receptor activation, thereby preventing receptor binding of IL-1 SI and IL-1 /I (27, 33, 34). Because of these properties IL-Ira has anti- inflammatory activity. From these in vitro results it can be concluded that IL-10, by inhibiting the effector functions of monocytes, PMN and eosinophils, has potent anti-inflammatory activities. In addition, through downregulation of chemokine production, IL-1 0 may also prevent migration and accumulation of these cells to sites of inflammation.

Ann Med 27

Ann

Med

Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

Uni

vers

itaet

s- u

nd L

ande

sbib

lioth

ek D

uess

eldo

rf o

n 08

/28/

13Fo

r pe

rson

al u

se o

nly.

11-1 0: Immunosuppression and Anti-inflammatory Properties 539

Regulation of 11-10 Production by Monocytes

Monocytes are important producers of 11-10 (26, 27). The production of IL-10 by monocytes (and also by T cells) occurs late after activation, compared to the rapid induction of proinflammatory cytokines and chemokines (4, 26, 27). This late production of IL-10 is consistent with the notion that IL-10 may function as a natural dampener of the immune response (12).

The production of IL-10 by monocytes is down- regulated by several other cytokines. IL-4, IL-13 and IFN-7 all suppress 11-1 0 production by activated monocytes (27, 35). Interestingly, IL-10 by itself also downregulates IL-1 0 mRNA expression in activated human monocytes, indicating that IL-10 has an important autoregulatory negative feedback activity (26, 27). Blocking studies carried out with neutralizing anti- IL-10 mAbs indicated that endogenously produced IL-10 indeed inhibits proinflammatory cytokine and chemokine production by these cells. In the presence of anti-IL-10 mAbs the production of these cytokines was considerably enhanced (26, 27).

11-10 Prevents Lethal Shock in Mice

IL-10 has also potent anti-inflammatory effects in vivo. At low concentrations of 1 lcg/mouse, it prevents lipo- polysaccharide-induced lethal shock in mice (36, 37). Administration of IL-10 up to 30 minutes after LPS injection still had protective effects (36). Measurement of macrophage-derived TNF-a, which has been implicated as the main mediator of toxic shock in this model, indicated that the circulating TNF-r levels were considerably reduced compared to those of non-IL-10 treated mice.

Consistent with its inhibitory effects on T-cell activation and cytokine production by these cells in vitro, IL-10 also inhibits T-cell activation and cytokine production in vivo, as demonstrated by its capacity to prevent lethal shock induced by the superantigen Staphylococcal enterotoxin B (SEB) (38). Administration of SEB to mice induces massive T-cell activation and cytokine production (including the production of pro- inflammatory cytokines) by these cells in vivo, which is lethal (38-40). In contrast to the LPS-induced shock model, the most important mediator of SEB-induced lethal shock is TNF-x produced by activated T cells (40). This T-cell-derived TNF-x is downregulated by IL-1 0, which is compatible with in vitro observations, which indicates that IL-1 0 inhibits the activity of mouse macrophages to activate T cells in the presence of SEB (41). From these data it is clear that IL-10 is very effective in preventing lethal shock in mice in vivo.

11-10 Deficient Mice Develop Chronic Inflammatory Bowel Disease

Mice rendered IL-1 O-deficient by targeting of the IL-10 gene have normal lymphocyte development and normal

antibody responses. However, most of these 11-10 knockout (KO) mice were growth retarded, anaemic and suffered from chronic inflammatory bowel disease (42). However, 11-1 O-deficient mice, kept in a specific pathogen-free environment, developed a much milder form of the disease. This indicates that IL-10 normally plays an important role in controlling the development of chronic inflammatory processes and that its absence results in chronic inflammatory responses (particularly in the gut), which are probably induced by normal enteric antigens. Administration of IL-10 to diseased IL- 1 O-deficient mice resulted in a dramatic improvement as judged by a strong reduction in the chronic inflammation of the gut, and their increase in weight and survival rates. In addition, 3-4-week-old IL-1 O-deficient mice treated with IL-10 remained healthy (D. Berg et al., unpublished).

IL-10 also inhibits inflammatory bowel disease in another mouse model. CB-17 severe combined immunodeficient (SCID) mice develop colitis spontaneously following transfer of CD4' memory T cells from BALB/c mice (43). This colitis could be prevented by administration of neutralizing anti-IFN-;, or anti-TNF-a mAbs, indicating that these cytokines are implicated in the pathogenesis of this disease (44). Administration of IL-10 protects these mice from colitis. Mice successfully treated with IL-10 had lower levels of IFN-7- and TNF-r mRNA expression in the colon compared to mice with colitis, suggesting that IL-10 prevents colitis, probably via inhibition of IFN-7 and TNF-z production (44). Collectively, these in vivo data indicate that IL-10 has therapeutic potential for the treatment of Crohn's disease and colitis in humans.

Phase I Studies of 11-10

IL-10 is well tolerated in humans. Intravenous single bolus injections of escalating doses of IL-10 given to healthy male volunteers revealed no adverse effects, even at doses of up to 25 pg/kg (45). No significant differences were observed in blood chemistry, urinalysis, haemoglobin concentrations, platelet counts, coagulation parameters, complement components or electrocardiograms of IL-1 O-treated and placebo- injected volunteers, Although IL-10 can stimulate the growth of activated B cells and lg production by these cells in vifro (46), no changes in serum lg levels were observed in 11-1 O-treated volunteers 96 hours after 11-10 administration. PBMNC of IL-1 O-treated volunteers, stimulated ex vivo with LPS, produced considerably lower levels of IL-1, IL-6 or TNF-a than PBMNC of placebo-treated individuals. These reduced levels of proinflammatory cytokine production persisted for 48 hours after injection (45) (C. Dinarello, unpublished results). Thus, a single injection of recombinant IL-10 in healthy humans is safe and well tolerated. In addition, the fact that the suppressive effects of IL-10 on pro- inflammatory cytokine production are relatively long-lasting indicates that daily treatment will not be required in the future use of IL-10 for therapy.

Ann Med 27

Ann

Med

Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

Uni

vers

itaet

s- u

nd L

ande

sbib

lioth

ek D

uess

eldo

rf o

n 08

/28/

13Fo

r pe

rson

al u

se o

nly.

540 de Vries

Potential Clinical Application of 11-10

The present data clearly indicate that IL-10 has potent immunosuppressive activities, both in vitro and in vivo. Comparison of the inhibitory effects of cyclosporin A (CsA) and IL-10 on antigen-specific proliferation of human T-cell clones in vitro indicated that IL-10, o n a per molar basis, was at least 100 times more effective than CsA (J. Chang and J. E. de Vries, unpublished). The capacity of IL-10 to downregulate the antigen- presenting and accessory cell function of monocytes, macrophages, Langerhans cells and dendritic cells, together with its direct inhibitory effect on T-cell activation, IL-2 production and T-cell expansion and its downregulation of proinflammatory cytokines and chemokine production and upregulation of the IL-1 ra, implies that IL-10 has great potential clinical utility in the general treatment of chronic inflammation, sepsis and autoimmune diseases. This latter notion is supported by the observations made in a mouse model for human type I insulin-dependent diabetes, which indicated that administration of IL-10 to nonobese diabetic (NOD) mice inhibited the onset of diabetes in these mice (47). The fact that IL-10 strongly downregulates the generation of alloresponsive T cells indicates that it may also have therapeutic value for the treatment of graft- versus-host disease (GVHD) and transplant rejection. Indeed, patients who spontaneously produce high levels of IL-10 prior to transplantations have no signs of GVHD after allogenic bone marrow transplantation, whereas the majority of patients who produce low IL-10 levels have severe GVHD and a high mortality (E. Holler and M. G. Roncarolo, unpublished). Apart from preventing GVHD in transplanted patients, there are strong indications that IL-10 may be important for the induction and maintenance of transplantation tolerance, because high levels of endogenous IL-10 production were observed in transplant patients in whom tolerance was achieved (48). The impressive beneficial effects of IL-10 on inflammatory bowel disease in different mouse models, and the lack of any adverse effects of high concentrations of IL-10 administered to healthy volunteers, suggest that IL-10 may be efficient in treating inflammatory bowel disease in man. Based on these observations and the fact that inflammatory bowel disease and Crohn’s disease cannot be adequately treated today, the first clinical trials using IL-10 in these diseases will be initiated in the very near future.

References

1. Mosmann TR, Coffman RT. Thl and Th2 cells: different patterns of lymphokine secretion lead to different functional properties. Annu Rev lmmunoll989; 7: 145-73.

2. Romagnani S. Lymphokine production by human T cells in disease states. Annu Rev lmmunol 1994; 12: 227-57.

3. Fiorentlno 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

4. Yssel H, de Waal Malefyt R, Roncarolo MG, Abrams JS, Lahesmaa R, de Vrles JE. IL-10 produced by subsets of

1989; 170: 2081 -5.

5.

6.

7.

8.

9.

10.

11.

12.

13.

14.

15.

16.

17.

18.

19

20

human CD4+ T cell clones and peripheral blood T cells. J lmmunoll992; 149: 2378-84. de Waal Malefyt R, Haanen J, Spits H, et al. Interleukin 10 (IL-1 0) and viral IL-10 strongly reduced antigen-specific human T cell proliferation by diminishing the antigen- presenting capacity of monocytes via down-regulation of class major histocompatibility complex expression. J Exp Med 1991; 174: 915-24. O’Garra A, Stapleton G, Dhar V, et al. Production of cytokines by mouse B cells: B lymphomas and normal B cells produce interleukin 10. lnt lmmunol 1990; 2: 821-32. Enk AH, Katz SI. Identification and induction of keratinocytes-derived IL-10. J lmmunol 1992; 149: 92-5. Burdin N, Peronne C, Banchereau J, Rousset F. Epstein- Barr virus transformation induces B lymphocytes to produce human interleukin 10. J Exp Med 1993; 177:

Benjamin D, Knobloch TJ, Dayton MA. Human B-cell lines derived from patients with acquired immuno- deficiency syndrome and Burkitt’s lymphoma constitutively secrete large quantities of interleukin-1 0. Blood 1992; 80:

Moore KW, O’Garra A, de Waal Malefyt R, Vieira P, Mosmann TR. Interleukin 10. Annu Rev lmmunol 1993; 11:

Vleira P, de Waal Malefyt R, Dang MN, et al. Isolation and expression of human cytokine synthesis inhibitory factor cDNA clones: homology to Epstein-Barr virus open reading frame BCRFI. Proc Natl Acad Sci USA 1991; 88:

de Waal Malefyt R, Yssel H, Roncarolo MG, Spits H, de Vries JE. Interleukin-10. Cum Opin lmmunol 1992; 4:

Ho ASY, Moore KW. Interleukin-10 and its receptor. Ther lmmunoll994; 1 : 173-85. June CH, Bluestone JA, Nadler LM, Thompson CB. The 87 and CD28 receptor families. lmmunol Today 1994; 15:

Azuma M, It0 D, Yaglta H, et al. 870 antigen is a second ligand for CTLA-4 and CD28. Nature 1993; 366: 76-9. Spits H, van Schooten W, Keizer H, et al. Alloantigen recognition is preceded by nonspecific adhesion of cytotoxic T cells and target cells. Science 1986; 232:

Matsul K, Boniface JJ, Reay PA, Schild H, Farekas de St Groth B, Davis MM. Low affinity interaction of peptide- MHC complexes with T cell receptors. Science 1991 ; 254:

Bejarano MT, de Waal Malefyt R, Abrams JS, et al. lnterleukin 10 inhibits allogeneic proliferative and cytotoxic T cell responses generated in primary lymphocyte cultures. lnt lmmunoll992; 4: 1389-97. Peguet-Navarro J, Moulon C, Caux C, Dalbiez-Gauthier C, Banchereau J, Schmltt D. Interleukin-1 0 inhibits the primary allogeneic T cell response to human epidermal Langerhans cells. Eur J lmmunol 1994; 24: 884-91. Caux C, Massacrier C, Vanbervllet B, Barthelemy C, Liu YJ, Banchereau J. Interleukin-1 0 inhibits T-cell alloreaction induced by human dendritic cells. lnt lmmunol 1994; 6:

295-304.

1289-98.

165-90.

1 172-6.

314-20.

321 -31.

403-5.

1788-91.

1 177-85. 21. Ding L, Linsley PS, Huang LY, Germaln RN, Shevach

EM. IL-10 inhibits macrophage costimulatory activity by selectively inhibiting the up-regulation of 87 expression. J lmmunoll993; 151 : 1224-34.

22. Wlllems F, Marchant A, Delville JP, et al. Interleukin-10 inhibits 87 and intercellular adhesion molecule-1 expression on human monocytes. Eur J lmmunoll994; 24:

23. Kubln MI Kamoun MI Kamoun M, Trlnchleri G. Interleukin 12 synergizes with B7/CD28 interaction in inducing efficient proliferation and cytokine production of human T cells. J

1007-9.

EX^ Med 1994; 180: 21 1-22.

Ann Med 27

Ann

Med

Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

Uni

vers

itaet

s- u

nd L

ande

sbib

lioth

ek D

uess

eldo

rf o

n 08

/28/

13Fo

r pe

rson

al u

se o

nly.

IL-1 0: Immunosuppression and Anti-inflammatory Properties 54 1

24. de Waal Malefyt R, Figdor C, de Vrles JE. Regulation of human monocyte functions by interleukin-10. In: de Vries JE, de Waal Malefyt R, eds. Interleukin 70. Austin, TX: R.G. Landes Company; 1995: 37-52.

25. de Waal Malefyt R, Yssel H, de Vrles JE. Direct effects of IL-10 on subsets of human CD4+ T cell clones and resting T cells. J lmmunol 1993; 150: 4754-65.

26. de Waal Malefyt R, Abrams J, Bennett B, Figdor CG, de Vries JE. lnterleukin 10 (IL-10) inhibits cytokine synthesis by human monocytes: an autoregulatory role of IL-10 produced by monocytes. J Exp Med 1991; 174: 1209-20.

27. de Waal Malefyt R, Flgdor C, Huljbens R, et al. Effects of IL-13 on phenotype, cytokine production, and cytotoxic function of human monocytes: Comparison to IL-4 and modulation by IFN-y or IL-10. J lmmunol 1993; 151:

28. Bagglollnl M, Dewald B, Dewald B, Moser B. Interleukin- 8 and related chemotactic cytokines - CXC and CC chemokines. Adv lmmunol1994; 55: 97-179.

29. Cassatella MA, Meda L, Bonora-Ceska M, Constantin G. Interleukin 10 (IL-10) inhibits the release of pro- inflammatory cytokines from human polymorphonuclear leukocytes. Evidence for an autocrine role of tumor necrosis factor and IL-1 beta in mediating the production of IL-8 triggered by lipopolysaccharide. J Exp Med 1993;

30. Kasama T, Strleter RM, Lukacs NW, Burdlck MD, Kunkel S.L. Regulation of neutrophil-derived chemokine expression by IL-10. J lmmunol 1994; 152: 3559-69.

31. Wang P, Wu P, Anther JC, Siege1 MI, Egan RW, Billah MM. Interleukin-1 0 inhibits interleukin-8 production in human neutrophils. Blood 1994; 83: 2678-83.

32. Takanaskl S, Nonaka R, Xlng Z, O’Byrne P, Dolovlch J, Jordana M. lnterleukin 10 inhibits lipopolysaccharide- induced survival and cytokines production by human peripheral blood eosinophils. J Exp Med 1994; 180: 71 1-5.

33. Jenkins JK, Malyak M, Arend WP. The effects of interleukin-1 0 on interleukin-1 receptor antagonist and interleukin-1 beta production in human monocytes and neutrophils. Lymphokine Cytokine Res 1994; 13: 47-54.

34. Cassatella MA, Meda L, Gasperlnl S, Calzettl F, Bonora S. lnterleukin 10 (IL-10) upregulates IL-1 receptor antagonist production from lipopolysaccharide-stimulated human polymorphonuclear leukocytes by delaying mRNA degradation. J Exp Med 1994; 179: 1695-9.

35. Chomarat P, Rlssoan M-C, Banchereau J, Mlossec R Interferon y inhibits interleukin 10 production by mono- cytes. J Exp Med 1993; 177: 523-7.

6370-81.

178: 2207-11.

36. Howard M, Muchamuel T, Andrade S, Menon S. lnterleukin 10 protects mice from lethal endotoxemia. J Exp Med 1993; 177: 1205-8.

37. Gerard C, Bruyns C, Marchant A, el al. Interleukin 10 reduces the release of tumour necrosis factor and prevents lethality in experimental endotoxemia. J Exp Med 1993;

38. Bean AG, Freiberg RA, Andrade S, Menon S, Zlotnik A. lnterleukin 10 protects mice against staphylococcal enterotoxin B-induced lethal shock. Infect lmmun 1993; 61 : 4937-9.

39. Drake CG, Kokln BL. Superantigens: biology, immunology and potential role in disease. J Clin lmmunol

40. Miethke 1, Wahl C, Heeg K, Echtenacher B, Krammer PH, Wagner H. T cell-mediated lethal shock triggered in mice by the superantigen staphylococcal enterotoxin B: critical role of tumour necrosis factor. J Exp Med 1992;

41. Florentlno DF, Zlotnlk A, Vlelra P, et al. IL-10 acts on the antigen presenting cell to inhibit cytokine production by Thl cells. J lmmunoll991; 146: 3444-51.

42. Kuhn R, Lohler J, Rennlck D, Rajewsky K, Muller W. Interleukin-10-deficient mice develop chronic enterocolitis. Cell 1993; 75: 263-74.

43. Powrle F, Leach MW, Mauze S, Caddle LB, Coffman RL. Phenotypically distinct subsets of CD4+ T cells induce or protect from chronic intestinal inflammation in C. 8-17 scid mice. Int Immunoll993; 5: 1461 -71.

44. Powrle F, Leach MW, Mauze S, Menon S, Caddle LB, Coffman RL. Inhibition of Thl responses prevents inflammatory bowel disease in SClD mice reconstituted with cd45rb”’ CD4+ T cells. Immunity 1994; 1: 553-62.

45. Chernoff, Granowllz EV, Shaplro L, et al. A phase I study of interleukin-10 in healthy humans: safety and effects on cytokine production. In: de Vries JE, de Waal Malefyt R, eds. Interleukin 70. Austin, TX: R.G. Landes Company;

46. Rousret F, Garcia E, Defrance T, et al. IL-10 is a potent growth and differentiation factor for activated human B lymphocytes. Proc Natl Acad Sci USA 1992; 89: 1890-3.

47. Pennllne KJ, Roque-Gaffney E, Monahan M. Recom- binant human IL-10 prevents the onset of diabetes in the nonobese diabetic mouse. Clin lmmunol lmmunopathol

48. Bacchetta R, Blgler M, Touralne J-L, et al. High levels of IL-10 production in vivo are associated with tolerance in a SClD patient transplanted with HLA mismatched hematopoietic stem cells. J Exp Med 1994; 179: 493-502.

177: 547-50.

1992; 12: 149-62.

175: 91 -8.

1995: 148-58.

1994; 71 : 169-75.

Ann Med 27

Ann

Med

Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

Uni

vers

itaet

s- u

nd L

ande

sbib

lioth

ek D

uess

eldo

rf o

n 08

/28/

13Fo

r pe

rson

al u

se o

nly.