Interleukin-1α-induced proteolytic activation of metalloproteinase-9 by human skin

Background. Increased activity of matrix metalloproteinase-9 (MMP-9) has been well documented in many diseases associated with inflammation, such as chronic wounds, bullous pemphigoid, liver failure, and tumor metastases. The mechanism for the proteolytic activation of pro-MMP-9 in human tissue still remains unknown. Methods. We investigated this mechanism through reconstitution of an inflammatory condition in normal human skin, and epidermal and dermal cells derived from skin. Normal human skin was cultured with exogenous cytokines associated with inflammation and tissue repair. MMP-9 induction and activation were measured, and potential mechanisms were probed by inhibitors. Reults. Pathophysiologic concentrations of interleukin (IL)-1 alpha rapidly induced pro-MMP-9 synthesis by human skin. In contrast, IL-1-induced activation of pro-MMP-9 was a slow process, which required 3 days. Tumor growth factor-beta induced pro-MMP-9 but failed to promote activation of the precursor. When the skin was stimulated with the combination of tumor growth factor-beta and IL-1 alpha, substantial induction and activation of pro-MMP-9 occurred. This IL-1 induced activation of pro-MMP-9 was observed in intact skin but not in isolated dermal fibrolasts or keratinocytes. IL-1-induced activation of pro-MMP-9 was inhibited by chymostatin, a chymotrypsinlike proteinase inhibitor. Furthermore, IL-1 alpha decreased tissue inhibitor of metalloproteinase 1 without changing MMP-9 activator activity. Conclusions. The proteolytic activation of pro-MMP-9 in skin inflammatory diseases likely occurs via a pathway including IL-alpha. The activation is mediated by downregulation of tissue inhibitor of MMP-1 and involves an as yet unidentified chymotrypsinlike proteinase.