Calmodulin differentially modulates the interleukin 1-induced biosynthesis of tissue inhibitor of metalloproteinases and matrix metalloproteinases in human uterine cervical fibroblasts.
The effects of a specific calmodulin inhibitor, N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7) on the synthesis of tissue inhibitor of metalloproteinases (TIMP) and precursor of matrix metalloproteinase 1/tissue collagenase (proMMP-1) and matrix metalloproteinase 3/stromelysin (proMMP-3), were examined using human uterine cervical fibroblasts in culture. When the cells were treated with human recombinant interleukin 1 alpha, the synthesis of TIMP, proMMP-1, and proMMP-3 was greatly enhanced along with the increase in the steady-state levels of mRNAs for respective proteins. The treatment of the cells with human recombinant interleukin 1 alpha and W-7 further augmented the production of proMMPs-1 and -3 and the accumulation of their mRNAs. In contrast, TIMP production and its steady-state mRNA level were reduced considerably under these conditions. Similar observations were made with another calmodulin inhibitor, trifluoperazine, but not with N-(6-aminohexyl)-1-naphthalenesulfonamide, the weakest inhibitor for calmodulin. These results indicate that calmodulin is required for the interleukin 1-enhanced synthesis of TIMP but it is a suppressor for the synthesis of proMMPs-1 and -3.
Ito
A
A
Department of Biochemistry, Tokyo College of Pharmacy, Japan.
Sato
T
T
Ojima
Y
Y
Chen
L C
LC
Nagase
H
H
Mori
Y
Y
D015152:Blotting, Northern; D015153:Blotting, Western; D002147:Calmodulin / Q000037:antagonists & inhibitors / Q000502:physiology*; D002584:Cervix Uteri / Q000201:enzymology*; D003238:Connective Tissue / Q000201:enzymology; D005109:Extracellular Matrix / Q000201:enzymology; D005260:Female; D015870:Gene Expression; D006023:Glycoproteins / Q000096:biosynthesis* / Q000276:immunology; D006801:Humans; D066298:In Vitro Techniques; D007375:Interleukin-1 / Q000494:pharmacology*; D020781:Matrix Metalloproteinase 1; D019278:Matrix Metalloproteinase 3; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors* / Q000096:biosynthesis* / Q000276:immunology; D003012:Microbial Collagenase / Q000096:biosynthesis*; D012333:RNA, Messenger / Q000235:genetics; D013449:Sulfonamides / Q000494:pharmacology; D019714:Tissue Inhibitor of Metalloproteinases; D014268:Trifluoperazine / Q000494:pharmacology
D002147:Calmodulin; D006023:Glycoproteins; D007375:Interleukin-1; D012333:RNA, Messenger; D013449:Sulfonamides; D019714:Tissue Inhibitor of Metalloproteinases; D014268:Trifluoperazine; C017967:W 7; C034700:N-(6-aminohexyl)-1-naphthalenesulfonamide; D008666:Metalloendopeptidases; D019278:Matrix Metalloproteinase 3; D003012:Microbial Collagenase; D020781:Matrix Metalloproteinase 1