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Cytokine blockade inhibits hepatic tissue inhibitor of metalloproteinase‐1 expression and up‐regulates matrix metalloproteinase‐9 in toxic liver injury
Author(s) -
Roderfeld Martin,
Geier Andreas,
Dietrich Christoph G.,
Siewert Elmar,
Jansen Bettina,
Gartung Carsten,
Roeb Elke
Publication year - 2006
Publication title -
liver international
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.873
H-Index - 110
eISSN - 1478-3231
pISSN - 1478-3223
DOI - 10.1111/j.1478-3231.2006.01271.x
Subject(s) - matrix metalloproteinase , proinflammatory cytokine , tumor necrosis factor alpha , medicine , liver injury , intraperitoneal injection , tissue inhibitor of metalloproteinase , cytokine , carbon tetrachloride , pharmacology , pathogenesis , interleukin , matrix metalloproteinase inhibitor , endogeny , inflammation , immunology , chemistry , endocrinology , organic chemistry
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)‐α or interleukin (IL)‐1β in mice led to an enhanced expression of hepatic TIMP‐1 after 4–16 h. Male Sprague–Dawley rats were treated with carbon tetrachloride (CCl 4 ) in the presence and absence of specific TNF‐α and IL‐1β inhibitors. Results: Real‐time PCR revealed a significant increase of TIMP‐1 mRNA in total rat liver 24 h after CCl 4 injection. Repetitive injection of both, etanercept and anakinra, before and after CCl 4 injection effectively inactivated TNF‐α and IL‐1β. Anticytokine pretreatment reduced the increase of TIMP‐1 expression after a single CCl 4 injection by 50% and 75%, respectively. In contrast to CCl 4 ‐treated rats with and without TNF‐α blockade, IL‐1β 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‐α and IL‐1β in rodents. Pharmacological inactivation of these cytokines significantly reduces TIMP‐1 gene expression. Our data provide a potential new antifibrotic approach.