Activation and induction of cytosolic phospholipase A2 by IL-1beta in human tracheal smooth muscle cells: role of MAPKs/p300 and NF-kappaB.
Cytosolic phospholipase A(2) (cPLA(2)) plays a pivotal role in mediating agonist-induced arachidonic acid (AA) release for prostaglandin (PG) synthesis during inflammation triggered by IL-1beta. However, the mechanisms underlying IL-1beta-induced cPLA(2) expression and PGE(2) synthesis in human tracheal smooth muscle cells (HTSMCs) remain unknown. IL-1beta-induced cPLA(2) protein and mRNA expression, PGE(2) production, or phosphorylation of p42/p44 MAPK, p38 MAPK, and JNK1/2, which was attenuated by pretreatment with the inhibitors of MEK1/2 (U0126), p38 MAPK (SB202190), and JNK1/2 (SP600125) or transfection with siRNAs of MEK1, p42, p38, and JNK2. IL-1beta-induced cPLA(2) expression was also inhibited by pretreatment with a NF-kappaB inhibitor, helenalin or transfection with siRNA of NIK, IKKalpha, or IKKbeta. IL-beta-induced NF-kappaB translocation was blocked by pretreatment with helenalin, but not U0126, SB202190, and SP600125. In addition, transfection with p300 siRNA blocked cPLA(2) expression induced by IL-1beta. Moreover, p300 was associated with the cPLA(2) promoter, which was dynamically linked to histone H4 acetylation stimulated by IL-1beta. These results suggest that in HTSMCs, activation of MAPKs, NF-kappaB, and p300 are essential for IL-1beta-induced cPLA(2) expression and PGE(2) secretion.
Lee
Chiang-Wen
CW
Division of Basic Medical Sciences, Department of Nursing, Chang Gung Institute of Technology, Chia-Yi, Taiwan.
Lee
I-Ta
IT
Lin
Chih-Chung
CC
Lee
Hui-Chun
HC
Lin
Wei-Ning
WN
Yang
Chuen-Mao
CM
D015232:Dinoprostone / Q000378:metabolism; D050881:E1A-Associated p300 Protein / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D004790:Enzyme Induction / Q000187:drug effects; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006801:Humans; D053583:Interleukin-1beta / Q000494:pharmacology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000201:enzymology*; D016328:NF-kappa B / Q000378:metabolism*; D054510:Phospholipases A2, Cytosolic / Q000096:biosynthesis* / Q000235:genetics; D010766:Phosphorylation / Q000187:drug effects; D011401:Promoter Regions, Genetic / Q000235:genetics; D014176:Protein Biosynthesis / Q000187:drug effects; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D014132:Trachea / Q000166:cytology*; D014158:Transcription, Genetic / Q000187:drug effects
D053583:Interleukin-1beta; D016328:NF-kappa B; D011518:Proto-Oncogene Proteins; D050881:E1A-Associated p300 Protein; C494360:EP300 protein, human; D048031:JNK Mitogen-Activated Protein Kinases; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D020930:MAP Kinase Kinase Kinases; C069937:MAP3K8 protein, human; D054510:Phospholipases A2, Cytosolic; D015232:Dinoprostone