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.