ROLE OF NITRIC-OXIDE IN DEPRESSED LYMPHOPROLIFERATIVE RESPONSES AND ALTERED CYTOKINE PRODUCTION FOLLOWING THERMAL-INJURY IN RATS

Immunodeficiency follows extensive burns. We investigated some underly ing mechanisms in rats, 10 days after a full-thickness skin burn affec ting 20% of total body surface area. In both normal and burned rats th e splenocyte proliferative response to Con A was linearly and negative ly correlated with nitric oxide (NO) production. In all burned rats, t he proliferative response was depressed by more than 80% and NO produc tion corresponded to a nitrite concentration above 20 mu M. Proliferat ive responses in burned rats were fully restored in the presence of 25 0 mu M N-G-monomethyl-L-arginine (NMMA). A time course study of NO pro duction in response to Con A, LPS, anti-CD3, and IFN-gamma showed that splenic macrophages from burned rats responded to direct and indirect stimuli more rapidly and more intensively than normal macrophages, In the second part of this work, the effect of the overproduction of NO on the synthesis of immunoregulatory and proinflammatory cytokines was investigated, Although it was inhibited, IFN-gamma production by sple nocytes from burned rats remained sufficient for NO synthase induction and was restored by NMMA. Concomitantly, IL-2 concentration was enhan ced but returned to normal in the presence of NMMA. TNF production was halved after burn injury and NMMA partially restored it. In contrast, IL-6 production was enhanced and increased further in the presence of NMMA. Therefore, cytokines were differently affected by burn injury a nd variously regulated by NO. (C) 1998 Academic Press.