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.
Napolitano
L M
LM
Department of Surgery, Baltimore VA Medical Center, Maryland, USA.
Campbell
C
C
Bass
B L
BL
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005264:Femoral Fractures / Q000378:metabolism*; D016753:Interleukin-10 / Q000096:biosynthesis / Q000276:immunology / Q000494:pharmacology; D015847:Interleukin-4 / Q000096:biosynthesis*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D011897:Random Allocation; D018805:Sepsis / Q000378:metabolism*; D013154:Spleen / Q000378:metabolism*; D013997:Time Factors
D000911:Antibodies, Monoclonal; D008070:Lipopolysaccharides; D016753:Interleukin-10; D015847:Interleukin-4