Activation and induction of cytosolic phospholipase A₂by IL‐1β in human tracheal smooth muscle cells: Role of MAPKs/p300 and NF‐κB

Abstract

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.