Aberrant signaling in the TNFalpha/TNF receptor 1 pathway of the NZM2410 lupus-prone mouse.

The purpose of this study was to evaluate the ability to induce TNFalpha-dependent apoptosis in vivo in predisease lupus-prone NZM2410 and derived B6.NZM congenic mouse strains. An endotoxicosis model that utilizes LPS and d-galactosamine to induce mortality by TNFalpha/TNFR1-dependent hepatocyte apoptosis was used to assess TNFalpha production, apoptotic signaling, and effects on the production of IL-6 and IL-10. NZM2410 was found to be resistant to endotoxicosis and to produce significantly less TNFalpha-induced IL-6 and IL-10. At low doses of LPS, partial resistance was associated with the Tnfa(w) allele. At higher doses of LPS, partial resistance cosegregated with lupus-susceptibility loci and functionally mapped downstream of caspase 3. Additional partial resistance in NZM2410 was also found upstream of FADD. These results demonstrate the existence of multiple defects in the TNFalpha/TNFR1 signaling pathway in the NZM2410 mouse and their relevance to lupus pathogenesis is discussed.