Cyclic adenosine 3',5'-monophosphate suppresses interleukin 1-induced synthesis of matrix metalloproteinases but not of tissue inhibitor of metalloproteinases in human uterine cervical fibroblasts.
Interleukin 1 (IL-1) mediates many cellular functions, but the signal transduction mechanisms of its actions are not clearly understood. Here, we have examined the exact participation of cAMP in the IL-1-induced production of the precursors of matrix metalloproteinase (MMPs) and their specific inhibitor, tissue inhibitor of metalloproteinases (TIMP) in human uterine cervical fibroblasts. IL-1 significantly augmented the production of proMMP-1 (vertebrate procollagenase), proMMP-3 (prostromelysin), and TIMP without detectable changes in the intracellular level of cAMP. Dibutyryl cAMP (Bt2cAMP) and the cAMP elevating agent (forskolin) did not replace IL-1 as MMP inducers. On the contrary, the IL-1-mediated induction of proMMP-1 and proMMP-3 was significantly suppressed by treatment of the cells with Bt2cAMP, forskolin, or theophylline. The suppressive effect of Bt2cAMP on the IL-1-induced production of proMMP-1 and -3 was not due to the inhibition of zymogen secretion, but resulted from the decrease in the steady-state levels of proMMP-1 and proMMP-3 mRNAs. In contrast, Bt2cAMP slightly enhanced the IL-1-induced production of TIMP. The synthesis of proMMP-2 (72-kDa progelatinase/type IV procollagenase) was not altered by IL-1 and/or Bt2cAMP. These results suggest, first, that induction of proMMP-1 and -3 synthesis may share similar transduction pathways but they are distinct from those for proMMP-2 and TIMP synthesis and, second, that cAMP does not function as a second messenger in the MMPs' induction upon IL-1 stimulation in human uterine cervical fibroblasts. Thus, it is further suggested that the system that increases the intracellular cAMP level may be involved in negative regulation of proMMP-1 and -3 production.
Takahashi
S
S
Department of Biochemistry, Tokyo College of Pharmacy, Japan.
Ito
A
A
Nagino
M
M
Mori
Y
Y
Xie
B
B
Nagase
H
H
D000818:Animals; D015153:Blotting, Western; D003994:Bucladesine / Q000494:pharmacology; D002584:Cervix Uteri / Q000201:enzymology*; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism*; D004792:Enzyme Precursors / Q000378:metabolism; D005109:Extracellular Matrix / Q000201:enzymology*; D005260:Female; D005347:Fibroblasts / Q000201:enzymology; D006023:Glycoproteins / Q000096:biosynthesis*; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology*; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D011817:Rabbits; D011863:Radioimmunoassay; D011994:Recombinant Proteins / Q000494:pharmacology; D013806:Theophylline / Q000494:pharmacology; D019714:Tissue Inhibitor of Metalloproteinases
D004792:Enzyme Precursors; D006023:Glycoproteins; D007375:Interleukin-1; D011994:Recombinant Proteins; D019714:Tissue Inhibitor of Metalloproteinases; D005576:Colforsin; D003994:Bucladesine; D013806:Theophylline; D000242:Cyclic AMP; D008666:Metalloendopeptidases