Transcriptional activation of fibroblast collagenase gene expression by a novel lymphokine, leukoregulin.

Leukoregulin (LR) is a novel T-cell derived cytokine with unique anti-tumor properties. We have recently demonstrated that LR is also able to modulate the biosynthetic repertoire of normal human skin fibroblasts in culture (Mauviel, A., Rédini, F., Hartmann, D.J., Pujol, J.-P., and Evans, C.H. (1991) J. Cell Biol. 113, 1455-1462). In this study, we have examined in detail the effects of LR on collagenase gene expression in human skin fibroblast cultures. The results indicated time- and dose-dependent induction of collagenase mRNA steady-state levels, the maximum elevation being approximately 35-fold. In contrast, the mRNA levels for tissue inhibitor of metalloproteases remained unchanged in the same RNA preparations. The enhancement of collagenase mRNA levels was shown to be dependent on protein synthesis, and it could be counteracted by dexamethasone or all-trans-retinoic acid. Transient transfections of cultured fibroblasts with a human collagenase promoter/reporter gene construct indicated up-regulation of the promoter activity, which could be blocked by dexamethasone and all-trans-retinoic acid. The observation suggested regulation at the transcriptional level of collagenase gene expression. LR was also shown to induce the mRNA levels for junB, suggesting possible involvement of the AP-1 complex in the regulation. The ability of LR to selectively induce collagenase gene expression in skin fibroblasts suggests that this cytokine may significantly contribute to the degradation of the extracellular matrix in physiological situations, such as tissue development and repair, and in diseases characterized by excessive degradation and turnover of collagen.