LIPOPOLYSACCHARIDE-INDUCED CYTOKINE CASCADE AND LETHALITY IN LT-ALPHATNF-ALPHA-DEFICIENT MICE/

Background: Tumor necrosis factor alpha (TNF-alpha) is often considere d the main proinflammatory cytokine induced by lipopolysaccharide (LPS ) and consequently the critical mediator of the lethality associated w ith septic shock. Materials and Methods: We used mice carrying a delet ion of both the lymphotoxin alpha (LT-alpha) and TNF-alpha genes to as sess the role of TNF in the cytokine cascade and lethality induced by LPS. Results: Initial production of IL-1 alpha, IL-1 beta, IL-6, and I L-10 is comparable in wild-type and mutant mice. However, at later tim es, expression of IL-1 alpha, IL-1 beta, and IL-10 is prolonged, where as that of IL-6 decreases in mutant mice. Expression of IFN-gamma is a lmost completely abrogated in mutants, which is in agreement with a mo re significant alteration of the late phase of the cytokine cascade. W e measured similar LD50 (600 mu g) for the intravenous injection of LP S in mice of the three genotypes (+/+, +/-, -/-), demonstrating that t he absence of TNF does not confer long-term protection from lethality. However, death occurred much more slowly in mutant mice, who were pro tected more efficiently from death by CNI 1493, an inhibitor of proinf lammatory cytokine production, than were wild-type mice. Discussion: T hus, while TNF-alpha is not required for the induction of these cytoki nes by LPS, it modulates the kinetics of their expression. The lethali ty studies simultaneously confirm a role for TNF as a mediator of earl y lethality and establish that, in the absence of these cytokines, oth er mediators take over, resulting in absence of long-term protection f rom LPS toxicity.