IL-1α is a potent stimulator of keratinocyte tissue plasminogen activator expression and regulated by TGF-β1

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AbstractsEpidermal keratinocytes synthesize and secrete tissue-type plasminogen activator. tPA converts the inactive precursor enzyme plasminogen into the trypsin like proteinase plasmin, and is an essential component of normal wound healing. tPA is not found in normal epidermis, but in keratinocytes at the leading edge of the wound. Proteolytic activity produced by tPA is necessary for the wound epidermis to cleave fibrin from its migratory pathway. However, the factors that regulate tPA expression in keratinocytes have remained largely elusive. In the present study, we sought to determine whether the cytokine interleukin-1α (IL-1α) and its regulator transforming growth factor β1 (TGF-β1), which are both commonly present in skin wounds, influence tPA production in cultured murine epidermal keratinocytes. We treated the keratinocytes with IL-1α in the absence or presence of TGF-β1 at various concentrations and analyzed the expression of tPA by RT-PCR, in situ hybridization, immunocytochemistry as well as immunofluorescence. We found that IL-1α induced mRNA and protein expression of tPA in a time and dose dependent manners. The maximal stimulation was seen at 72 h and 100 U/ml. However, treatment of keratinocytes with TGF-β1 partially inhibited IL-1α induced expression of tPA mRNA in dose dependent manners and the maximal inhibition was seen at 60 ng/ml. Our findings could explain tPA generation in wound epidermis is at least partially controlled by changes in local IL-1α activity, and will contribute to our understanding the physiological effects of IL-1α and TGF-β1 as well as their interaction of with the PA system during skin wound healing.

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