Cytokine blockade inhibits hepatic tissue inhibitor of metalloproteinase‐1 expression and up‐regulates matrix metalloproteinase‐9 in toxic liver injury

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Abstract
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. 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. 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. 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.