Soluble TNFR II/IgG1 Fc fusion protein treatment in the LPS-mediated septic shock of rats.

ABSTRACT

Tumor necrosis factor-alpha (TNF-alpha) is thought to play a major role in systemic inflammation associated with sepsis. A potent TNF antagonist, a recombinant fusion protein that consists of the soluble TNF receptor (p75) linked to the Fc portion of human IgG1 (sTNFR II/IgG1 Fc fusion protein, sTNFRFc), has been shown to provide rapid and sustained improvement in local inflammation diseases by binding TNF-alpha and preventing its proinflammatory activities. To explore the potential therapeutic efficacy for septic shock of sTNFRFc, we investigate the effect of this molecule on the survival rate, blood pressure, serum TNF-alpha bioactivity as well as the expression of TNF-alpha at mRNA level in the liver in a LPS-induced rat septic shock model. Blood pressure of the rats was monitored by multi-channel creature signal analysis system. Serum TNF-alpha level and bioactivity was assessed using an enzyme-linked immunoassay and a L929 cytotoxicity assay, respectively. The expression of TNF-alpha mRNA in liver was examined by semi-quantitative RT-PCR. sTNFRFc administered to rats 24h before LPS challenge ablated the rise in serum TNF-alpha bioactivity that occurs in response to LPS and protected against hypotension and death. These results indicate that TNF-alpha is a mediator of fatal septic shock, and suggest that sTNFRFc offer a potential therapy of systemic infection.