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Title: Acute tumor necrosis factor-alpha-induced liver injury in the absence of tumor necrosis factor receptor-associated factor 1 gene expression.

Authors: Pryhuber, Gloria S; Huyck, Heidie L; Roper, Jason M; Cornejo, Judith; O'Reilly, Michael A; Pierce, Robert H; Tsitsikov, Erdyni N

Published In Am J Pathol, (2005 Jun)

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

PubMed ID: 15920149 Exiting the NIEHS site

MeSH Terms: Animals; Blotting, Western; Chemical and Drug Induced Liver Injury; Female; Gene Expression; In Situ Nick-End Labeling; Injections, Intraperitoneal; Injections, Intravenous; Kupffer Cells/drug effects; Liver Diseases/etiology*; Liver Diseases/pathology; Liver/drug effects; Liver/pathology; Lung Diseases/chemically induced; Lung Diseases/complications*; Lung Diseases/pathology; Lung/drug effects; Lung/pathology; Male; Mice; Mice, Knockout; Tumor Necrosis Factor Receptor-Associated Peptides and Proteins/deficiency*; Tumor Necrosis Factor-alpha/administration & dosage*; Tumor Necrosis Factor-alpha/analysis; Tumor Necrosis Factor-alpha/metabolism*

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