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Abstract

Matrix metalloproteinases (MMPs) are responsible for degradation of extracellular matrix and play important roles in cell migration, proliferation, and tissue remodeling related to airway inflammation. Interleukin-1β (IL-1β) has been shown to induce MMP-9 production in many cell types and contribute to airway inflammatory responses. However, the mechanisms underlying MMP-9 expression induced by IL-1β in human tracheal smooth muscle cells (HTSMCs) remain unclear. Here, we investigated the roles of p42/p44 MAPK, p38 MAPK, JNK, and NF-κB pathways for IL-1β-induced MMP-9 production in HTSMCs. IL-1β induced production of MMP-9 protein and mRNA in a time- and concentration-dependent manner determined by zymographic, Western blotting, and RT-PCR analyses, which was attenuated by inhibitors of MEK1/2 (U0126), p38 MAPK (SB202190), JNK (SP600125), and NF-κB (helenalin), and transfection with dominant negative mutants of MEK1/2, p38 and JNK, respectively. IL-1β-stimulated phosphorylation of p42/p44 MAPK, p38 MAPK, and JNK was attenuated by pretreatment with U0126, SB202190, SP600125, or transfection with these dominant negative mutants of MEK, ERK, p38 and JNK, respectively. Furthermore, IL-1β-stimulated translocation of NF-κB into the nucleus and degradation of IκB-α was blocked by helenalin. Finally, the reporter gene assay revealed that MAPKs and NF-κB are required for IL-1β-induced MMP-9 luciferase activity in HTSMCs. MMP-9 promoter activity was enhanced by IL-1β in HTSMCs transfected with MMP-9-Luc, which was inhibited by helenalin, U0126, SB202190, and SP600125. Taken together, the transcription factor NF-κB, p42/p44 MAPK, p38 MAPK, and JNK that are involved in MMP-9 expression in HTSMCs exposed to IL-1β have now been identified. J. Cell. Physiol. 211: 759–770, 2007. © 2007 Wiley-Liss, Inc.