Interleukin-1beta induces MMP-9 expression via p42/p44 MAPK, p38 MAPK, JNK, and nuclear factor-kappaB signaling pathways in human tracheal smooth muscle cells.
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.
Liang
Kao-Chih
KC
Department of Physiology and Pharmacology, Chang Gung University, Kwei-San, Tao-Yuan, Taiwan.
Lee
Chiang-Wen
CW
Lin
Wei-Ning
WN
Lin
Chih-Chung
CC
Wu
Chou-Bin
CB
Luo
Shue-Fen
SF
Yang
Chuen-Mao
CM
D002478:Cells, Cultured; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000502:physiology; D006801:Humans; D053583:Interleukin-1beta / Q000494:pharmacology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D020780:Matrix Metalloproteinase 9 / Q000235:genetics* / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D016328:NF-kappa B / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011401:Promoter Regions, Genetic / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D014132:Trachea / Q000166:cytology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D053583:Interleukin-1beta; D016328:NF-kappa B; D012333:RNA, Messenger; D048031:JNK Mitogen-Activated Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases; D020780:Matrix Metalloproteinase 9