Mechanism of enhanced susceptibility to sepsis following hemorrhage. Interleukin-10 suppression of T-cell response is mediated by eicosanoid-induced interleukin-4 release

A. Ayala, D. L. Lehman, C. D. Herdon and I. H. Chaudry
Department of Surgery, Michigan State University, East Lansing.

OBJECTIVES: To determine (1) whether interleukin-10 (IL-10) contributes to depressed T-cell responses observed following hemorrhage and (2) what effect other immunosuppressive agents known to play a role in hemorrhage have on IL-10 release. DESIGN: Hemorrhage was induced in C3H/HeN mice. The mice were resuscitated and then killed 2 hours after hemorrhage to obtain plasma, splenocytes, splenic macrophages, and splenic T cells. RESULTS AND CONCLUSIONS: Decreased splenocyte/T-cell proliferation was associated with enhanced release of IL-10 by cells from hemorrhaged mice. However, unlike T cells, IL-10 release by macrophages was not comparatively elevated. While no changes were seen in systemic plasma levels of IL-10, the role of IL-10 as a localized immunosuppressant was demonstrated by the ability of IL-10 monoclonal antibody to restore T-cell proliferation following hemorrhage. Furthermore, elevated IL-10 release was prevented by the addition of ibuprofen or monoclonal antibody against transforming growth factor beta or IL-6. Since these agents have direct or indirect influences on prostanoid synthesis, studies were carried out examining the capacity of varying concentrations of prostaglandin E2 (PGE2) to augment IL-10 release by murine cloned Th2 cells (D10.G4.1) and by T cells from sham-operated or hemorrhaged mice. While the addition of PGE2, 10(-9) mol/L, potentiated the release of IL-10, this effect appears to be indirect, since the incorporation of monoclonal antibody to IL-4 prevented the release of IL-10 by PGE2-treated cells from sham-operated or hemorrhaged mice. Such a mechanism of eicosanoid-induced IL-4/IL-10 cell-mediated immunosuppression may directly contribute to the decreased capacity to ward off infectious challenge seen following hemorrhage.

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