Lipopolysaccharide-induced cytokine production and mortality in mice treated with Corynebacterium parvum

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Abstract
Tumor necrosis factor a (TNF-α) has been shown to be an important mediator of the lethal effects of endotoxin in several experimental models of septic shock. However, studies with a recombinant human interleukin-1 (IL-1) receptor antagonist protein (IL-lra) suggest a role for IL-1 as a mediator of septic shock as well. In the present study, we show that mice treated in vivo with Corynebacterium parvum are primed for the production of interferon-γ (IFN-γ) and exhibit an enhanced capacity to produce serum IL-Ια, TNF-a, and IL-6 when challenged intravenously with lipopolysaccharide (LPS). The majority of C. parvum -treated mice die within 24 h of an LPS challenge. Pretreatment with a rat antimouse TNF-α monoclonal antibody (mAb) protected 90% of the animals against the lethal endotoxin challenge, while an anti-IFN-γ mAb gave approximately 75% protection. The anti-IFN-7fgamma; mAb also caused a reduction in LPS- induced serum TNF-α and IL-Ια. Anti-IL-la, anti- IL-1β, and anti-IL-6 neutralizing mAb did not protect against lethality when administered to mice prior to the LPS challenge. These results indicate that TNF-α and IFN-γ are major mediators of endotoxin shock in C. parvum-treated mice. The results further suggest that the IFN-γ produced by C. parvum-primed mice in response to an LPS challenge serves as a stimulus for enhanced production of TNF-α and IL-Ια. These findings are consistent with an increasing body of evidence suggesting a major role for IFN-γ in lethal endotoxemia.

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