TNF‐α induces diaphragm dysfunction and oxidative stress through TNF receptor 1

Abstract

Tumor necrosis factor-α (TNF) is an inflammatory cytokine present at high levels in sepsis, cancer, and other chronic diseases, where it acts as a major regulator of muscle weakness and wasting. Previously, we showed that TNF depresses force and increases cytosolic oxidant levels in mouse diaphragm. It was unclear whether these responses were induced via the TNF type 1 (TNFr1) or type 2 receptor (TNFr2). TNFr1 contains an apoptotic death domain and can stimulate cell signaling through a nonapoptotic pathway involving increased reactive oxygen species. Therefore, we hypothesized that TNFr1 knockout mice would be protected from TNF mediated contractile dysfunction and oxidative stress. One hour after an intraperitoneal injection of TNF 100 μg kg−1, maximal diaphragm force from TNFr2 −/− and control animals was lowered ~25% vs. vehicle-treated animals (p<0.05), while TNF had no effect on TNFr1 −/− diaphragm force (p>0.4). DCFH oxidant assay showed TNF-stimulated cytosolic oxidant production was lower in TNFr1 −/− diaphragm vs. wild type controls (81.9 ± 4.1% of control; p<0.01), while cytosolic oxidant activity in TNF-treated TNFr2 −/− animals did not differ from controls (p>0.9). These results support the hypothesis that TNF contractile dysfunction and oxidative stress are regulated through TNFr1. Current work focuses on potential molecular targets of TNF damage. Supported by HL59878