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(American Journal of Pathology. 2005;166:1637-1645.)
© 2005 American Society for Investigative Pathology

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

Gloria S. Pryhuber^*, Heidie L. Huyck^*, Jason M. Roper, Judith Cornejo, Michael A. O’Reilly^*, Robert H. Pierce and Erdyni N. Tsitsikov

From the Departments of Pediatrics,^* Environmental Medicine, and Pathology, University of Rochester School of Medicine and Dentistry, Rochester, New York; and the Division of Immunology, Children’s Hospital and Department of Pediatrics, Harvard Medical School, Boston, Massachusetts

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

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