Interleukin-1alpha-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.


RESULTS
Pathophysiologic concentrations of interleukin (IL)-1alpha 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-1alpha, 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 fibroblasts or keratinocytes. IL-1-induced activation of pro-MMP-9 was inhibited by chymostatin, a chymotrypsinlike proteinase inhibitor. Furthermore, IL-1alpha 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-1alpha. The activation is mediated by downregulation of tissue inhibitor of MMP-1 and involves an as yet unidentified chymotrypsinlike proteinase.
Han
Yuan-Ping
YP
Division of Plastic and Reconstructive Surgery, University of Southern California, Los Angeles, CA 90033, USA.
Downey
Susan
S
Garner
Warren L
WL
D002918:Chymotrypsin / Q000378:metabolism; D017364:Collagenases / Q000378:metabolism; D020405:Dermis / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D004789:Enzyme Activation / Q000187:drug effects; D004792:Enzyme Precursors / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D007375:Interleukin-1 / Q000378:metabolism* / Q000494:pharmacology; D015603:Keratinocytes / Q000187:drug effects / Q000201:enzymology; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D009924:Organ Culture Techniques; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D012871:Skin Diseases / Q000378:metabolism*; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism
D004792:Enzyme Precursors; D007375:Interleukin-1; D019715:Tissue Inhibitor of Metalloproteinase-1; D002918:Chymotrypsin; D017364:Collagenases; C120487:pro-matrix metalloproteinase 9; D020780:Matrix Metalloproteinase 9