title: Cytokine blockade inhibits hepatic tissue inhibitor of metalloproteinase-1 expression and up-regulates matrix metalloproteinase-9 in toxic liver injury.
abstract: BACKGROUND
  Tissue inhibitor of metalloproteinases (TIMP)-1, the most important endogenous inhibitor of matrix metalloproteinases, plays a pivotal role in the pathogenesis of liver fibrosis and may represent an effective therapeutic target in the design of antifibrotic strategies for chronic liver diseases.
  
  
  METHODS
  Intraperitoneal application of a single dose of either tumor necrosis factor (TNF)-alpha or interleukin (IL)-1beta in mice led to an enhanced expression of hepatic TIMP-1 after 4-16 h. Male Sprague-Dawley rats were treated with carbon tetrachloride (CCl4) in the presence and absence of specific TNF-alpha and IL-1beta inhibitors.
  
  
  RESULTS
  Real-time PCR revealed a significant increase of TIMP-1 mRNA in total rat liver 24 h after CCl4 injection. Repetitive injection of both, etanercept and anakinra, before and after CCl4 injection effectively inactivated TNF-alpha and IL-1beta. Anticytokine pretreatment reduced the increase of TIMP-1 expression after a single CCl4 injection by 50% and 75%, respectively. In contrast to CCl4-treated rats with and without TNF-alpha blockade, IL-1beta inactivation caused a sevenfold increase in matrix metalloproteinases-9 mRNA levels.
  
  
  CONCLUSIONS
  In conclusion, TIMP-1 expression is up-regulated in the early phase of toxic liver injury by proinflammatory cytokines such as TNF-alpha and IL-1beta in rodents. Pharmacological inactivation of these cytokines significantly reduces TIMP-1 gene expression. Our data provide a potential new antifibrotic approach.
authors.affiliation: Department of Gastroenterology (Medical Clinic 11), University Hospital, Justus-Liebig-University, Giessen, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Roderfeld
authors.forename: Andreas
authors.initials: A
authors.lastname: Geier
authors.forename: Christoph G
authors.initials: CG
authors.lastname: Dietrich
authors.forename: Elmar
authors.initials: E
authors.lastname: Siewert
authors.forename: Bettina
authors.initials: B
authors.lastname: Jansen
authors.forename: Carsten
authors.initials: C
authors.lastname: Gartung
authors.forename: Elke
authors.initials: E
authors.lastname: Roeb
mesh_terms: D000818:Animals; D002251:Carbon Tetrachloride; D016207:Cytokines / Q000008:administration & dosage / Q000494:pharmacology*; D004195:Disease Models, Animal; D000068800:Etanercept; D007074:Immunoglobulin G / Q000008:administration & dosage / Q000494:pharmacology; D053590:Interleukin 1 Receptor Antagonist Protein / Q000008:administration & dosage / Q000494:pharmacology; D053583:Interleukin-1beta / Q000037:antagonists & inhibitors*; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000378:metabolism*; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D051381:Rats; D017207:Rats, Sprague-Dawley; D018124:Receptors, Tumor Necrosis Factor / Q000008:administration & dosage; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000037:antagonists & inhibitors*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*; D015854:Up-Regulation / Q000187:drug effects* / Q000235:genetics
chemical_list: D016207:Cytokines; D007074:Immunoglobulin G; D053590:Interleukin 1 Receptor Antagonist Protein; D053583:Interleukin-1beta; D018124:Receptors, Tumor Necrosis Factor; D019715:Tissue Inhibitor of Metalloproteinase-1; D014409:Tumor Necrosis Factor-alpha; D002251:Carbon Tetrachloride; D020780:Matrix Metalloproteinase 9; D000068800:Etanercept