Interleukin-1[beta] induces interstitial collagenase gene
expression and protein secretion in renal mesangial cells.
Daphna-Iken, Dorit, and Aubrey R. Morrison.
Department of Medicine and Molecular Biology and Pharmacology,
Washington University School of Medicine, St. Louis, MO 63110
APStracts 2:0108F, 1995.
Degradation and tissue remodeling of the extracellular matrix in the
normal glomerulus occurs through the coordinate action of neutral
metalloproteinases which are in turn regulated by specific
inhibitors. Many of these proteins can be secreted by mesangial
cells. In the current study, gene regulation of a rat matrix
metalloproteinase, interstitial collagenase and its tissue inhibitor
of metalloproteinase-1 (TIMP-1), were investigated by Northern blot
analysis. Stimulation of rat mesangial cell (RMC) collagenase by IL
-1[beta] produced an increase (>45-fold) in mRNA which peaked at
12 hrs. Lesser effects on the TIMP-1 mRNA expression were observed in
response to IL-1[beta]. Indomethacin did not influence the effect of
IL-1[beta] on collagenase, and exogenous PGE2 had no significant
effect either on basal or IL-1[beta] stimulated mRNA levels.
Collagenase was secreted into the media and showed minimal
gelatinolytic activity at 36 hrs stimulation with IL-1[beta] by
zymography. By Western immunoblotting we demonstrated with 24 hrs of
stimulation the secretion of the active form of collagenase which
further increased after 36 hrs with IL-1[beta] when compared to the
control. When RMC were retreated with genistein and herbimycin A,
they both inhibited collagenase mRNA induction by IL-1[beta]. These
data suggest that IL-1[beta] stimulates interstitial collagenase
synthesis and activation, and that a tyrosine kinase pathway is
involved in the signal transduction mechanisms and is not dependent
on endogenous prostaglandin biosynthesis. Recently, a third
interstitial collagenase (collagenase-3) has been identified from
breast carcinoma. This cDNA is 84% identical to the rat interstitial
collagenase cDNA probe we have utilized in this study and thus may
represent the rat homologue of the human collagenase-3 now called
MMP-13.
Received 3 March 1995; accepted in final form 13 June 1995.
APS Manuscript Number F74-5.
Article publication pending Am. J. Physiol. (Renal Fluid Electrolyte
Physiology).
ISSN 1080-4757 Copyright 1995 The American Physiological Society.
Published in APStracts on 11 July 1995.