Distinct roles of tumor necrosis factor-alpha and nitric oxide in acute liver injury induced by carbon tetrachloride in mice.
Macrophages are known to release a number of different inflammatory mediators with cytotoxic potential. In the present studies we analyzed the role of two macrophage-derived mediators, tumor necrosis factor-alpha (TNF-alpha) and nitric oxide, in liver injury induced by carbon tetrachloride (CCl4). Treatment of mice with CCl4 resulted in a dose- and time-dependent induction of centrilobular hepatic necrosis. This was observed within 12 h with 0.3 ml/kg CCl4 and was correlated with increases in serum transaminase levels. CCl4 administration also caused increases in hepatic TNF-alpha mRNA expression and serum TNF-alpha levels, as well as inducible nitric oxide synthase (NOS II) protein expression in the liver. To study the role of TNF-alpha and nitric oxide in hepatotoxicity, we used knockout mice lacking the gene for the 55-kDa TNF-alpha receptor (TNFR1/p55), the TNF-alpha cytokine, or NOS II. We found that CCl4 was significantly less effective in inducing hepatotoxicity in mice lacking TNFR1/p55 or the TNF-alpha cytokine. In contrast, CCl4-induced liver injury was increased in knockout mice lacking the gene for NOS II. This was associated with an increase in hepatic TNF-alpha mRNA expression and serum TNF-alpha levels. These data suggest that the hepatoprotective effects of nitric oxide in this model may be due in part to inhibition of TNF-alpha.
Environmental and Occupational Health Sciences Institute, Rutgers University and the University of Medicine and Dentistry of New Jersey- Robert Wood Johnson Medical School, Piscataway, New Jersey 08854, USA.
L A
LA
Morio
H
H
Chiu
K A
KA
Sprowles
P
P
Zhou
D E
DE
Heck
M K
MK
Gordon
D L
DL
Laskin
D000208:Acute Disease; D000818:Animals; D015153:Blotting, Western; D002251:Carbon Tetrachloride / Q000633:toxicity*; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism* / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D005260:Female; D008099:Liver / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009569:Nitric Oxide / Q000235:genetics / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D012313:RNA / Q000302:isolation & purification; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013045:Species Specificity; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*
D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D012313:RNA; D002251:Carbon Tetrachloride; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse