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IL‐1β‐induced expression of cytosolic phospholipase A 2 in human synovial fibroblast of rheumatoid arthritis
Author(s) -
Chi PeiLing,
Yang ChuenMao
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.1121.11
Subject(s) - p38 mitogen activated protein kinases , phospholipase a2 , small hairpin rna , transfection , proinflammatory cytokine , eicosanoid , microbiology and biotechnology , chemistry , small interfering rna , inflammation , cytosol , phosphorylation , biology , arachidonic acid , immunology , biochemistry , protein kinase a , enzyme , gene knockdown , apoptosis , gene
Arachidonyl‐selective cytosolic phospholipase A 2 (cPLA 2 ) is most likely the rate‐liming step in eicosanoid generation. The products of arachidonic acid metabolism are key mediatorsof inflammatory responses in rheumatoid arthritis andyet we do not know the mechanisms of their regulation. We therefore studied the regulation of this pivotal cPLA 2 enzyme to generate inflammatory PGE 2 in human synovial fibroblasts by pro‐inflammatory cytokines. We demonstrated a dose‐ and time‐dependent expression of cPLA 2 protein and mRNA and PGE 2 synthesis by IL‐1β which were inhibited by the inhibitors of p38 (SB202190) and JNK (SP600125), respectively. Consistently, IL‐1β‐stimulated phosphorylation of p38 and JNK was attenuated by pretreatment with SB202190 or SP600125, respectively. Transfection with short hairpin RNA (shRNA) of p38 and JNK also abolished IL‐1β‐induced cPLA 2 expression, indicating the involvement of p38 and JNK in these responses. Furthermore, IL‐1β‐induced cPLA 2 expression and PGE 2 synthesis was significantly blocked by a NF‐κB inhibitor Bay11‐7082 and by transfection with dominant negative plasmids of NIK, IKKα or IKKβ. As expected, IL‐1β‐stimulated translocation of NF‐κB into the nucleus was partially blocked by Bay11‐7082, SB202190 or SP600125. Taken together, we conclude that IL‐1β‐induced cPLA 2 expression then up‐regulatedinflammatory PGE 2 level through p38, JNK, NF‐κB pathways.