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-a (TNF-alpha), are elevated in many lung diseases, causing local inflammation, fever, and multiorgan, including hepatic, dysfunction. Cellular responses to TNF-a 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-a. Despite relatively mild lung injury, intratracheal TNF-alpha-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-a levels were strikingly elevated in TRAF1 -/- mice. Pretreatment with neutralizing anti-TNFRI antibody significantly reduced liver injury and serum TNF-a. Cells isolated by bronchoalveolar lavage from intratracheally treated TRAF1-/- mice produced more TNF-a than cells from treated wildtype mice, suggesting that lung cells contributed to elevated serum TNF-a. These studies suggest that TRAF1 provides negative feedback for TNF-a synthesis and limits TNFRI-mediated systemic effects of TNF-alpha originating in the lung.