Regulation of tissue inhibitor of metalloproteinases-1 gene expression by cytokines and dexamethasone in rat hepatocyte primary cultures

Hepatology. 1993 Dec;18(6):1437-42.

Abstract

The steady-state levels of extracellular matrix proteins are regulated by the rates of their synthesis and degradation. Metalloproteinases and their specific inhibitors, tissue inhibitor of metalloproteinases-1 and -2 are believed to play a crucial role in extracellular matrix protein degradation. Here we show that the tissue inhibitor of metalloproteinases-1 is expressed in rat hepatocytes in primary culture and regulated by inflammatory cytokines. Rat hepatocytes constitutively express mRNA of tissue inhibitors of metalloproteinases-1 at a low level. Incubation with conditioned medium from lipopolysaccharide-stimulated human monocytes led to a dramatic induction of mRNA of tissue inhibitors of metalloproteinases-1. The inflammatory cytokines interleukin-1 beta, interleukin-6, interleukin-11, leukemia inhibitory factor and ciliary neurotrophic factor were also capable of stimulating expression of mRNA of tissue inhibitors of metalloproteinases-1. Among these cytokines interleukin-6 was the most potent stimulator. The combination of interleukin-1 beta, interleukin-6 and interleukin-11 synergistically up-regulated mRNA of tissue inhibitors of metalloproteinases-1. The synthetic glucocorticoid dexamethasone dose dependently inhibited constitutive and interleukin-6-induced expression of tissue inhibitors of metalloproteinases-1. A possible involvement of tissue inhibitor of metalloproteinases-1 in the pathogenesis of liver fibrosis and cirrhosis is discussed.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Cytokines / pharmacology*
  • Dexamethasone / pharmacology*
  • Gene Expression Regulation*
  • Glycoproteins / genetics*
  • Interleukin-1 / pharmacology
  • Interleukin-11 / pharmacology
  • Interleukin-6 / pharmacology
  • Liver / cytology
  • Liver / drug effects*
  • Liver / metabolism
  • Male
  • Metalloendopeptidases / antagonists & inhibitors*
  • RNA, Messenger / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Tissue Inhibitor of Metalloproteinases

Substances

  • Cytokines
  • Glycoproteins
  • Interleukin-1
  • Interleukin-11
  • Interleukin-6
  • RNA, Messenger
  • Tissue Inhibitor of Metalloproteinases
  • Dexamethasone
  • Metalloendopeptidases