Previous studies suggest that excessive activation of macrophages and overproduction of TNF might be involved in the inflammatory lesions of the lung and skin in me/me mice. We recently demonstrated that Fas-mediated apoptosis in LPS-activated macrophages results in down modulation of TNF production. Therefore, we propose that the Fas signaling defect in me/me macrophages might lead to defective activation-induced apoptosis and overproduction of TNF. Northern Blot analysis revealed a 20-fold increase in the expression of TNF-RI and TNF-RH in the lung and skin of me/me mice compared to wild-type mice. Newborn me/me mice treated with a TNF binding protein (TNF-bp); 5 μg/g qOD, capable of blocking the binding of TNF to their receptors, led to a 100% survival of me/me mice at 4 weeks of age, compared to no survival in the control group. Treatment with TNF-bp prevented the development of the "motheaten" skin patches, pneumonitis and vasculitis in me/me mice compared to controls. The glomerulonephritis was also decreased as demonstrated by reduced levels of proteinuria in TNF-bp treated me/me mice. TNF-bp did not correct the hematopoietic developmental defects in me/me mice. The level of IgM autoantibody and the abnormal phenotype of spleen cells was similar to that of untreated control mice. These results indicate that overexpression of TNF is involved in the pathogenesis of inflammatory disease in me/me mice, resulting in tissue damage and early mortality. Our results also suggest that lung, skin, and kidney disease in me/me mice is due to defective Fas apoptosis signaling and over-utilization of the TNF-TNFR pathway which is not related to autoantibody production since TNF-bp reduces disease but not autoantibodv production.