Acute tumor necrosis factor-alpha-induced liver injury in the absence of tumor necrosis factor receptor-associated factor 1 gene expression.
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.
Pryhuber
Gloria S
GS
Department of Pediatrics, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA. gloria_pryhuber@urmc.rochester.edu
Huyck
Heidie L
HL
Roper
Jason M
JM
Cornejo
Judith
J
O'Reilly
Michael A
MA
Pierce
Robert H
RH
Tsitsikov
Erdyni N
EN
D000818:Animals; D015153:Blotting, Western; D056486:Chemical and Drug Induced Liver Injury; D005260:Female; D015870:Gene Expression; D020287:In Situ Nick-End Labeling; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D007728:Kupffer Cells / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008107:Liver Diseases / Q000209:etiology* / Q000473:pathology; D008168:Lung / Q000187:drug effects / Q000473:pathology; D008171:Lung Diseases / Q000139:chemically induced / Q000150:complications* / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins / Q000172:deficiency*; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage* / Q000032:analysis / Q000378:metabolism*
D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins; D014409:Tumor Necrosis Factor-alpha