Suppression of the allogeneic response by human IL-10: a critical role for suppression of a synergy between IL-2 and TNF-alpha.
The effect of IL-10 on T-cell activation by alloantigens in primary mixed lymphocyte reaction (MLR) was examined. IL-10 strongly suppressed proliferation and cytokine synthesis observed in this reaction. To determine the cytokine synthesis inhibition that was critical for the IL-10 induced suppression of proliferation in MLR, the effect of exogenous cytokines (IL-1 alpha, IL-1 beta, IL-2, IL-4, IL-6, IFN-gamma, or TNF-alpha) on this suppression was examined. None of these cytokines, when used at high concentration, was able to completely restore proliferation in the MLR to the levels observed in the absence of IL-10. However, IL-2 and TNF-alpha, when added alone at high concentration, could partially overcome the IL-10 induced suppression of proliferation in MLR. Moreover, when a combination of IL-2 and TNF-alpha was added at suboptimal doses to IL-10-suppressed MLR, complete restoration of the proliferative response was obtained. The ability of IL-10 to suppress proliferation in MLR was dependent on the type of cells used as stimulators. Thus, IL-10 suppressed proliferation in MLR when allogeneic normal peripheral blood mononuclear cells (PBMC), highly purified monocytes or B cells, were used, but not when B-cell lines were used as stimulators. Investigation of the effect of IL-10 on cytokine synthesis revealed that when B-cell lines were used as stimulators of MLR, IL-10 suppressed IFN-gamma and IL-2 synthesis but was unable to suppress TNF-alpha production. In contrast, CSA, which inhibited proliferation in MLR induced by B-cell lines, also inhibited TNF-alpha. IL-2 and IFN-gamma synthesis. Together these data suggest that the suppression of MLR by IL-10 requires the effective inhibition of both IL-2 and TNF-alpha production to suppress a synergy between these two cytokines.
Tadmori
W
W
Immunology Department, Schering-Plough Research Institute, Kenilworth, NJ 07033.
Zhang
M
M
Beavis
A J
AJ
Sullivan
L M
LM
Narula
S K
SK
D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001402:B-Lymphocytes / Q000276:immunology*; D002478:Cells, Cultured; D004357:Drug Synergism; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006681:HLA-D Antigens / Q000096:biosynthesis; D006801:Humans; D007108:Immune Tolerance; D007371:Interferon-gamma / Q000494:pharmacology; D007376:Interleukin-2 / Q000494:pharmacology*; D015850:Interleukin-6 / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects; D007959:Lymphocyte Culture Test, Mixed; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D000911:Antibodies, Monoclonal; D006681:HLA-D Antigens; D007376:Interleukin-2; D015850:Interleukin-6; D015375:Receptors, Interleukin-2; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma