Kinetics of splenocyte interleukin-4 production after injury and lethal endotoxin challenge

Cytokine aberrations may contribute to sepsis-associated mortality after trauma. We have previously documented that IL-10 (a Th-2 cytokine) is downregulated after tissue trauma, and the administration of exogenous IL-10 improved survival and anti-IL-10 antibody increased lethality in a murine injury-lethal endotox-emia model. IL-4 activates the Th-2 subset of T cells, and functions in a paracrine manner to inhibit proinflammatory cytokine synthesis. The purpose of this study was to investigate the kinetics of IL-4 production in this murine trauma-sepsis model. Mice (n = 50) were randomized to five groups: Control, Femur Fracture (FFx), FFx-lipopolysaccharide (LPS), FFx-LPS-IL10, and FFx-LPS-Anti-IL10. LPS (400 micrograms ip) was administered 4 days after FFx to induce lethal sepsis. IL-10 (0.5 microgram ip) or anti-IL-10 (100 micrograms IP) was administered at resuscitation, 30 min after LPS. IL-4 production was measured in ex vivo splenocyte culture supernatants at 24-hr intervals. Splenocyte IL-4 production was significantly upregulated in the FFx-LPS 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 group that received exogenous IL-10; however, a subsequent rapid decline was documented. Treatment with anti-IL-10 antibody after FFx injury and septic challenge with LPS is associated with an upregulation of splenocyte IL-4 synthesis, as well as an increase in mortality in this murine model. IL-4 and IL-10 interaction postinjury may profoundly influence monocyte activation, cell-mediated immunity, and the subsequent host immune response to infection.