Group IIA secretory phospholipase A(2) stimulates inducible nitric oxide synthase expression via ERK and NF-kappaB in macrophages.

Abstract

The mammalian group IIA secretory phospholipase A2 (sPLA2) is believed to play an important role in inflammation and cell injury. The present study underlines the importance of group IIA sPLA2 in the regulation of iNOS. Treatment of cells with sPLA2 induced protein expression and mRNA accumulation of iNOS in a dose‐dependent manner. The pretreatment of cells with ρ‐BPB or SCA, selective sPLA2 inhibitors, inhibited sPLA2‐induced iNOS expression. sPLA2 stimulated the simultaneous activation of two classes of mitogen‐activated protein kinases ERK and JNK, but did not stimulate p38 MAPK. PD98059, a selective MEK inhibitor, inhibited sPLA2‐induced nitrite production and iNOS expression as well as ERK phosphorylation. In addition, pretreatment of ρ‐BPB or SCA also resulted in inhibition of sPLA2‐induced ERK phosphorylation. The sPLA2 signaling mechanisms involving the activation of transcription factor NF‐κB were studied in the same cells. That stimulation of cells with sPLA2 caused NF‐κB activation in a time‐dependent manner was shown by the detection of NF‐κB‐specific DNA‐protein binding and by IκBα degradtion. sPLA2‐induced NF‐κB activation was prevented in the presence of ρ‐BPB. Furthermore, the NF‐κB inhibitor PDTC suppressed sPLA2‐induced nitrite production and iNOS expression as well as IκBα degradation. The results strongly suggest that group IIA sPLA2 induces iNOS in macrophages and that this induction occurs through ERK and NF‐κB.