IL-10 mediation of activation-induced Th-1 cell apoptosis and lymphoid dysfunction in polymicrobial sepsis

Recent studies suggest that increased activation-induced lymphocyte apoptos is (AICD) is detected in mouse splenocytes during polymicrobial sepsis whic h may contribute to lymphocyte immune dysfunction [i,e,, decreased interleu kin (IL-)2 and interferon-gamma (IFN-gamma) production] leading to the asso ciated morbidity seen in those animals. Thus, we wanted to examine the hypo thesis that immune suppressive agents, such as IL-4, IL-10 or prostaglandin E-2 (PGE(2)), known to be elevated in septic animals, also contribute to t his increase in AICD, Here we demonstrate that the inclusion of monoclonal antibody (mAb) to IL-10, but not anti-IL-4 or ibuprofen (IBU), blunted this sepsis induced increase in splenocyte AICD, Additionally, septic mice defi cient in the IL-10 gene product(-/-) showed neither an increase in AICD nor a loss of IL-2/IFN-gamma release capacity. Interestingly, mAb to IL-10 did not altered the extent of AICD in a Th-2-cell line, but exogenous IL-10 di d potentiate Th-1-like cell line AICD, This was consistent with the finding that the increased AICD seen in septic mouse splenocytes was restricted la rgely to the CD4(+) cells producing IL-2 (Th-1-cells) and that mAb to IL-10 treatment suppressed this change. Furthermore, IL-10 appears to mediate it s AICD effect by upregulation of the Fas receptor and Fas receptor signalin g protein components, but not by altered expression of Bcl/Bax/Bad family m embers, in septic mouse splenocytes, To the extent that these processes con tribute in a pathological fashion to the animal's capacity tee survive seps is we have previously observed that in vivo post-treatment of mice with mAb IL-10 markedly attenuated septic mortality. Collectively, these data indic ate that in the septic mouse the Th-2 cytokine IL-10 not only serves to act ively induce Th-1 lymphocyte immune dysfunction but also plays a role in th eir apoptotic depletion. These processes in turn appear to contribute to th e animal's inability to ward off lethal septic challenge. (C) 2001 Academic Press.