Interleukin‐1β induces MMP‐9 expression via p42/p44 MAPK, p38 MAPK, JNK, and nuclear factor‐κB signaling pathways in human tracheal smooth muscle cells

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-1beta (IL-1beta) 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-1beta in human tracheal smooth muscle cells (HTSMCs) remain unclear. Here, we investigated the roles of p42/p44 MAPK, p38 MAPK, JNK, and NF-kappaB pathways for IL-1beta-induced MMP-9 production in HTSMCs. IL-1beta 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-kappaB (helenalin), and transfection with dominant negative mutants of MEK1/2, p38 and JNK, respectively. IL-1beta-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-1beta-stimulated translocation of NF-kappaB into the nucleus and degradation of IkappaB-alpha was blocked by helenalin. Finally, the reporter gene assay revealed that MAPKs and NF-kappaB are required for IL-1beta-induced MMP-9 luciferase activity in HTSMCs. MMP-9 promoter activity was enhanced by IL-1beta in HTSMCs transfected with MMP-9-Luc, which was inhibited by helenalin, U0126, SB202190, and SP600125. Taken together, the transcription factor NF-kappaB, p42/p44 MAPK, p38 MAPK, and JNK that are involved in MMP-9 expression in HTSMCs exposed to IL-1beta have now been identified.

TRAIL induces MMP-9 expression via ERK activation in human astrocytoma cells

“…MAPKs are regarded as important signal mediators for MMP-9 expression in various cell types and stimuli. The phorbol 12-myristate 13-acetate induces MMP-9 expression in human astrocytoma cells through activation of ERK and JNK [27], and interleukin-1b induces MMP-9 expression in human smooth muscle cell via ERK, JNK, and p38 MAPK activation [29]. In this study, we demonstrated that TRAIL activates the ERK pathway, and that inhibition of ERK activation blocks TRAIL-induced MMP-9 expression in human astrocytoma cells.…”

Down-Regulation of Organic Anion Transporter Expression in Human Hepatocytes Exposed to the Proinflammatory Cytokine Interleukin 1β

“…Taken together, these data do not support a major role of ERK in IL-1␤-mediated down-regulation of transporters. Besides ERK, other MAPKs such as the p38 MAPKs and c-Jun N-terminal kinase contribute to IL-1␤ effects (Liang et al, 2007;Ogata et al, 2007). Interestingly, we have found that these two MAPKs were activated by IL-1␤ in both human hepatocytes and HepaRG cells (data not shown).…”

The Antagonistic Actions of Endogenous Interleukin-1β and 15-Deoxy-Δ12,14-prostaglandin J2 Regulate the Temporal Synthesis of Matrix Metalloproteinase-9 in Sheared Chondrocytes

“…This activation pattern is in line with previously published data showing that IL-1␤ induces MMP-9 expression via a PI3K (38)-, ERK1/2 (39)-, and JNK (40)-dependent pathway in rat brain astrocytes and rat cardiac fibroblasts. Interestingly, IL-1␤ has been reported to up-regulate MMP-9 expression via a p38-/ERK1/2-/JNK-dependent pathway in human tracheal smooth muscle cells (41). The lack of involvement of p38 in shear-induced MMP-9 expression in human chondrocytes as opposed to IL-1␤-treated smooth muscle cells may be due to cell type differences.…”