SRC-RELATED TYROSINE KINASES REGULATE TRANSCRIPTIONAL ACTIVATION OF THE INTERSTITIAL COLLAGENASE GENE, MMP-1, IN INTERLEUKIN-1-STIMULATED SYNOVIAL FIBROBLASTS

Objective. To characterize tyrosine kinases that contribute to the tra nscription of interstitial collagenase. Methods. Four thousand six hun dred fourteen basepairs of the rabbit collagenase promoter region were cloned and sequenced. Plasmids containing collagenase promoter fragme nts linked to the luciferase reporter gene were transiently transfecte d into primary rabbit synovial fibroblasts. Regulation of gene activat ion by inflammatory mediators and tyrosine kinase inhibitors was asses sed. To identify specific tyrosine kinases that contribute to collagen ase gene expression, v-src was transiently expressed in rabbit synovia l fibroblasts along with collagenase promoter constructs, and basal an d interleukin-1 (IL-1)-induced collagenase transcription was assayed. Results. An inhibitor of are-related tyrosine kinases, herbimycin A, i nhibited increases of collagenase messenger RNA in IL-1- and phorbol m yristate acetate-treated fibroblasts. Transcriptional activation of co llagenase by IL-1 was also inhibited by herbimycin A. Expression of v- src in synovial fibroblasts enhanced basal and IL-1-inducible transcri ption. Conclusion. Activation of collagenase transcription by inflamma tory mediators involves activation of an src-related tyrosine kinase.