Acute Tumor Necrosis Factor-α-Induced Liver Injury in the Absence of Tumor Necrosis Factor Receptor-Associated Factor 1 Gene Expression

Pulmonary and serum levels of tumor necrosis factor-α (TNF-α), are elevated in many lung diseases, causing local inflammation, fever, and multiorgan, including hepatic, dysfunction. Cellular responses to TNF-α are determined by recruitment of specific proteins to intracellular receptor signaling complexes. One of these proteins, TNF receptor-associated factor 1 (TRAF1), is highly regulated in pulmonary cells. To determine the effect of reduced pulmonary TRAF1 expression, TRAF1-null (−/−) and control, BALB/c (wild-type), mice were treated intratracheally, intraperitoneally, or intravenously, with TNF-α. Despite relatively mild lung injury, intratracheal TNF-α-treated TRAF1−/− mice exhibited marked liver injury with an approximate fivefold increase in serum liver enzyme levels as compared to wild-type mice. In addition, serum TNF-α levels were strikingly elevated in TRAF1−/− mice. Pretreatment with neutralizing anti-TNFRI antibody significantly reduced liver injury and serum TNF-α. Cells isolated by bronchoalveolar lavage from intratracheally treated TRAF1−/− mice produced more TNF-α than cells from treated wild-type mice, suggesting that lung cells contributed to elevated serum TNF-α. These studies suggest that TRAF1 provides negative feedback for TNF-α synthesis and limits TNFRI-mediated systemic effects of TNF-α originating in the lung.