Inhibition of interleukin 1-induced biosynthesis of stromelysin by the calcium antagonist TMB-8 (8-(N, N-diethylamino)octyl-3,4,5-trimethoxybenzoate HCl).
This study was done to identify agents that can inhibit interleukin 1 (IL1)-induced stromelysin biosynthesis and to gain insight into the mechanism of IL1 action. For this purpose, various agents known to modulate calcium-dependent signal transduction pathway were evaluated in rabbit synovial fibroblast (RSF) cultures. Only the conditioned medium from RSF treated with the intracellular calcium antagonist TMB-8 (8-(N,N-diethylamino)-octyl 3,4,5-trimethoxybenzoate hydrochloride) had significantly lower proteoglycan-degrading metalloproteinase activity than controls. Biosynthetic labeling, immunoprecipitation and immunohistochemical studies, using a polyclonal antibody against rabbit stromelysin, demonstrated that TMB-8 inhibited synthesis stromelysin, the proteoglycan-degrading matrix metalloproteinase. Further evaluation of the TMB-8 effect revealed that the compound had no effect on secretion and that it was not acting by preventing activation of the proenzyme or by inhibiting the enzyme activity. These results suggest that TMB-8 may be inhibiting stromelysin synthesis by limiting intracellular calcium levels.
Baragi
V M
VM
Department of Immunopathology, Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company, Ann Arbor, Michigan 48105, USA.
Sweet
A M
AM
Thompson
M A
MA
Hawkins
K L
KL
Toy
K A
KA
Rosebury
W S
WS
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020013:Calcium Signaling / Q000187:drug effects* / Q000502:physiology; D002478:Cells, Cultured; D002614:Chelating Agents / Q000494:pharmacology; D017077:Culture Media, Conditioned / Q000494:pharmacology; D003593:Cytoplasm / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism*; D005707:Gallic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology*; D007150:Immunohistochemistry; D007375:Interleukin-1 / Q000037:antagonists & inhibitors* / Q000378:metabolism* / Q000494:pharmacology; D007476:Ionophores / Q000494:pharmacology; D019278:Matrix Metalloproteinase 3 / Q000096:biosynthesis* / Q000187:drug effects; D008985:Monensin / Q000494:pharmacology; D011509:Proteoglycans / Q000378:metabolism; D011817:Rabbits; D013583:Synovial Membrane / Q000187:drug effects / Q000378:metabolism
D000906:Antibodies; D002121:Calcium Channel Blockers; D002614:Chelating Agents; D017077:Culture Media, Conditioned; D007375:Interleukin-1; D007476:Ionophores; D011509:Proteoglycans; C006014:8-(N,N-diethylamino)octyl-3,4,5-trimethoxybenzoate; D005707:Gallic Acid; D008985:Monensin; D019278:Matrix Metalloproteinase 3