Role of TGF-β1 and TNF-α in IL-1β mediated activation of proMMP-9 in pulmonary artery smooth muscle cells: Involvement of an aprotinin sensitive protease

We investigated the role of TGF-β1 and TNF-α in mediating the effect of IL-1β in activating proMMP-9 and proMMP-2, and the involvement of an aprotinin sensitive protease in this scenario in bovine pulmonary artery smooth muscle cells. IL-1β induces TGF-β1 mediated stimulation of 92 kDa proMMP-9 and 72 kDa proMMP-2 mRNA and protein expression; whereas, the elevated level of TNF-α promotes activation of proMMP-9 and proMMP-2. Interestingly, TNF-α induced activation of proMMP-9 appeared to be mediated via a 43 kDa aprotinin sensitive protease. TNF-α inhibited aprotinin and TIMP-1 mRNA and protein expression, which apparently facilitated the proteolytic conversion of proMMP-9 to MMP-9 with the involvement of the aprotinin sensitive protease. The aprotinin sensitive protease did not activate proMMP-2 under IL-1β stimulation, albeit a marked inhibition of TIMP-2 mRNA and protein expression were elicited by TNF-α. Thus, IL-1β induced stimulation of the two progelatinases occurs via different mechanisms.

► TGF-β1 and TNF-α mediate IL-1β induced expression and activation of proMMP-9 and proMMP-2.
► TGF-β1 up regulates mRNA and protein expression of proMMP-9 and proMMP-2.
► TNF-α down regulates mRNA and protein expression of aprotinin, TIMP-1 and TIMP-2.
► TNF-α stimulates an aprotinin sensitive protease via its de novo protein synthesis.
► ProMMP-9, but not proMMP-2, activation by IL-1β occurs via the serine protease.