KINETICS OF SPLENOCYTE INTERLEUKIN-4 PRODUCTION AFTER INJURY AND LETHAL ENDOTOXIN CHALLENGE

Cytokine aberrations may contribute to sepsis-associated mortality aft er trauma. We have previously documented that IL-10 (a Th-2 cytokine) is downregulated after tissue trauma, and the administration of exogen ous IL-10 improved survival and anti-IL-10 antibody increased lethalit y in a murine injury-lethal endotoxemia model. IL-4 activates the Th-2 subset of T cells, and functions in a paracrine manner to inhibit pro inflammatory cytokine synthesis. The purpose of this study was to inve stigate the kinetics of IL-4 production in this murine trauma-sepsis m odel. Mice (n = 50) were randomized to five groups: Control, Femur Fra cture (FFx), FFx-lipopolysaccharide (LPS), FFx-LPS-IL10, and FFx-LPS-A nti-IL10. LPS (400 mu g ip) was administered 4 days after FFx to induc e lethal sepsis. IL-10 (0.5 mu g ip) or anti-IL-10 (100 mu g IP) was a dministered at resuscitation, 30 min after LPS. IL-4 production was me asured in ex vivo splenocyte culture supernatants at 24-hr intervals. Splenocyte IL-4 production was significantly upregulated in the FFx-LP S group that received anti-IL-10; maximal IL-4 production was on Day 5 , with a greater than sevenfold increase compared to all other groups. A transient early rise in IL-4 production was noted in the FFx-LPS gr oup that received exogenous IL-10; however, a subsequent rapid decline was documented. Treatment with anti-IL-10 antibody after FFx injury a nd septic challenge with LPS is associated with an upregulation of spl enocyte IL-4 synthesis, as well as an increase in mortality in this mu rine model. IL-4 and IL-10 interaction postinjury may profoundly influ ence monocyte activation, cell-mediated immunity, and the subsequent h ost immune response to infection. (C) 1997 Academic Press.