MECHANISM OF ENHANCED SUSCEPTIBILITY TO SEPSIS FOLLOWING HEMORRHAGE -INTERLEUKIN-10 SUPPRESSION OF T-CELL RESPONSE IS MEDIATED BY EICOSANOID-INDUCED INTERLEUKIN-4 RELEASE

Objectives: To determine (1) whether interleukin-10 (IL-10) contribute s to depressed T-cell responses observed following hemorrhage and (2) what effect other immunosuppressive agents known to play a role in hem orrhage have on IL-10 release. Design: Hemorrhage was induced in C3H/H eN mice. The mice were resuscitated and then killed 2 hours after hemo rrhage to obtain plasma, splenocytes, splenic macrophages, and splenic T cells. Results and Conclusions: Decreased splenocyte/T-cell prolife ration was associated with enhanced release of IL-10 by cells from hem orrhaged mice. However, unlike T cells, IL-10 release by macrophages w as not comparatively elevated. While no changes were seen in systemic plasma levels of IL-10, the role of IL-10 as a localized immunosuppres sant was demonstrated by the ability of IL-10 monoclonal antibody to r estore T-cell proliferation following hemorrhage. Furthermore, elevate d IL-10 release was prevented by the addition of ibuprofen or monoclon al antibody against transforming growth factor beta or IL-6. Since the se agents have direct or indirect influences on prostanoid synthesis, studies were carried out examining the capacity of varying concentrati ons of prostaglandin E(2) (PGE(2)) to augment IL-10 release by murine cloned T(h)2 cells (D10.G4.1) and by T cells from sham-operated or hem orrhaged mice. While the addition of PGE(2), 10(-9) mol/L, potentiated the release of IL-10, this effect appears to be indirect, since the i ncorporation of monoclonal antibody to IL-4 prevented the release of I L-10 by PGE(2)-treated cells from sham-operated or hemorrhaged mice. S uch a mechanism of eicosanoid-induced IL-4/IL-10 cell-mediated immunos uppression may directly contribute to the decreased capacity to ward o ff infectious challenge seen following hemorrhage.