PLA(2) phosphorylation and cyclooxygenase-2 induction, through p38 MAP kinase pathway, is involved in the IL-1 beta-induced bradykinin B-2 receptor gene transcription

We hypothesized that inflammatory mediators such as interleukin-1 beta (IL- 1 beta) might be responsible for the hyperreactivity to bradykinin observed in asthmatic patients. We reported previously that Il-1 beta induced a pro stanoid-dependent increase in the density of bradykinin B-2 receptors in cu ltured human bronchial smooth muscle cells. Our experiments demonstrate tha t the rapid prostaglandin E-2 (PGE(2)) synthesis induced by IL-1 beta is ab olished by cycloheximide, suggesting the involvement of protein synthesis. The formation of PGE(2) is preceded by the phosphorylation of cPLA(2) and t he expression of cyclooxygenase-2 (Cox-2). The inhibition of p38 MAP kinase inhibited PGE2 synthesis, cPLA2 phosphorylation and abolished Cox-2 expres sion. The inhibition of Cox-2 expression correlated with a decrease of brad ykinin B2 receptor expression. These data demonstrate that the activation o f p38 MAP kinase elicited by IL-1 beta leads to the phosphorylation of cPLA (2) and Cox-2 overexpression, allowing rapid synthesis of PGE(2) as a prere quisite for bradykinin B-2 gene expression in human bronchial smooth muscle cells which could explain the hyperresponsiveness of asthmatic patients to bradykinin.