INTERLEUKIN-1-BETA INDUCTION OF TISSUE INHIBITOR OF METALLOPROTEINASE(TIMP-1) IS FUNCTIONALLY ANTAGONIZED BY PROSTAGLANDIN E(2) IN HUMAN SYNOVIAL FIBROBLASTS
Ja. Dibattista et al., INTERLEUKIN-1-BETA INDUCTION OF TISSUE INHIBITOR OF METALLOPROTEINASE(TIMP-1) IS FUNCTIONALLY ANTAGONIZED BY PROSTAGLANDIN E(2) IN HUMAN SYNOVIAL FIBROBLASTS, Journal of cellular biochemistry, 57(4), 1995, pp. 619-629
Elevated levels of tissue inhibitor of metalloproteases-l (TIMP-1) hav
e been demonstrated in inflamed synovial membranes, and it is believed
that the inhibitor may play a critical role in the regulation of conn
ective tissue degradation. The present study was undertaken to define
the cellular mechanism of action of the inflammatory mediators, interl
eukin-1 beta (IL-1 beta) and prostaglandin E(2) (PGE(2)), in the contr
ol of TIMP-1 synthesis and expression in human synovial fibroblasts. R
ecombinant human IL-1 beta induced a time- and dose-dependent saturabl
e response in terms of TIMP-1 mRNA expression (effective concentration
for 50% maximal response, EC(50) = 31.5 +/- 3.3 pg/ml) and protein sy
nthesis (EC(50) = 30 +/- 3.3 pg/ml). The protein kinase C (PKC) inhibi
tors, H-7, staurosporine, and calphostin C, reversed the rhIL-1 beta i
nduction of TIMP-1 mRNA. PGE(2) also inhibited rhIL-1 beta-stimulated
TIMP-1 mRNA expression and protein secretion in a dose-dependent fashi
on. The concentration of PGE(2) necessary to block 50% of rhIL-1 beta-
stimulated TIMP-1 secretion, IC50, was 1.93 ng/ml (4.89 nM). Forskolin
, and other stable derivatives of cAMP, mimicked, to a large extent, t
he effects of PGE(2). The phorbol ester, PMA, up-regulated considerabl
y the mRNA expression of TIMP-1 but had no effect on protein productio
n. Calphostin C substantially reduced PMA-activated TIMP-1 expression.
Staurosporine, calphostin C, H-7, and substances that elevate cellula
r levels of cAMP, like PGE(2), also reduced basal expression and synth
esis of TIMP-1. Taken together, the data suggest that PKA and C may me
diate opposing effects in terms oi TIMP-1 expression and secretion in
human synovial fibroblasts. (C) 1995 Wiley-Liss, Inc.