Macrophage migration inhibitory factor in drug-induced liver injury: a role in susceptibility and stress responsiveness.
Idiosyncratic drug-induced hepatitis may depend upon many factors including a balance between pro- and anti-inflammatory mediator production levels. Using a guinea pig model of liver injury induced by bioactivation of the anesthetic drug, halothane, we found that toxicity was commensurate with an increase in serum macrophage migration inhibitory factor (MIF), a pro-inflammatory signal and counter-regulator of glucocorticoids, but only in susceptible animals. The pathogenic role of MIF was further investigated using a murine model in which liver injury was induced by the reactive metabolite of another drug, acetaminophen (APAP). MIF leakage from the liver into the sera preceded peak increases in toxicity following APAP administration. MIF null (-/-) mice were significantly less susceptible to this toxicity at 8 h. At 48 h following a 300 mg/kg dose, complete lethality was observed in wild-type mice, while 46% survival was noted in MIF-/- mice. The decreased hepatic injury in MIF-/- mice correlated with a reduction in mRNA levels of interferon-gamma and a significant increase in heat shock protein expression, but was unrelated to the APAP-protein adduct formation in the liver. These findings support MIF as a critical pro-toxicant signal in drug-induced liver injury with potentially important and novel effects on heat shock protein responsiveness.
Bourdi
Mohammed
M
Molecular and Cellular Toxicology Section, Laboratory of Molecular Immunology, National Heart, Lung, and Blood Institute, National Institutes of Health, 9000 Rockville Pike, Bldg. 10, Rm. 8N110 Bethesda, MD 20892-1760, USA. bourdim@nih.gov
Reilly
Timothy P
TP
Elkahloun
Abdel G
AG
George
John W
JW
Pohl
Lance R
LR
D000082:Acetaminophen; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D015415:Biomarkers / Q000032:analysis / Q000097:blood; D001711:Biotransformation; D056486:Chemical and Drug Induced Liver Injury / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D020022:Genetic Predisposition to Disease; D006168:Guinea Pigs; D006221:Halothane; D006360:Heat-Shock Proteins / Q000032:analysis / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008263:Macrophage Migration-Inhibitory Factors / Q000097:blood* / Q000172:deficiency / Q000235:genetics; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000378:metabolism; D015996:Survival Rate
D015415:Biomarkers; D006360:Heat-Shock Proteins; D018836:Inflammation Mediators; D008263:Macrophage Migration-Inhibitory Factors; D012333:RNA, Messenger; D000082:Acetaminophen; D007371:Interferon-gamma; D000410:Alanine Transaminase; D006221:Halothane