Abstract
Arachidonyl‐selective cytosolic phospholipase A2 (cPLA2) 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 cPLA2 enzyme to generate inflammatory PGE2 in human synovial fibroblasts by pro‐inflammatory cytokines. We demonstrated a dose‐ and time‐dependent expression of cPLA2 protein and mRNA and PGE2 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 cPLA2 expression, indicating the involvement of p38 and JNK in these responses. Furthermore, IL‐1β‐induced cPLA2 expression and PGE2 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 cPLA2 expression then up‐regulatedinflammatory PGE2 level through p38, JNK, NF‐κB pathways.
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