Protein kinase C? regulates nuclear translocation of extracellular signal-regulated kinase, which contributes to bradykinin-induced cyclooxygenase-2 expression.

ABSTRACT: The proinflammatory mediator bradykinin stimulated cyclooxygenase-2 (COX-2) expression and subsequently prostaglandin E₂ synthesis in dermal fibroblasts. The involvement of B2 receptors and G?q in the role of bradykinin was suggested by using pharmacological inhibitors. The PKC activator PMA stimulated COX-2 mRNA expression. Bradykinin failed to induce COX-2 mRNA expression in the presence of PKC inhibitors, whereas the effect of bradykinin was observed in the absence of extracellular Ca²⁺. Bradykinin-induced COX-2 mRNA expression was inhibited in cells transfected with PKC? siRNA. These observations suggest that the novel PKC? is concerned with bradykinin-induced COX-2 expression. Bradykinin-induced PKC? phosphorylation and COX-2 mRNA expression were inhibited by an inhibitor of 3-phosphoinositide-dependent protein kinase-1 (PDK-1), and bradykinin-induced PDK-1 phosphorylation was inhibited by phospholipase D (PLD) inhibitors, suggesting that PLD/PDK-1 pathway contributes to bradykinin-induced PKC? activation. Pharmacological and knockdown studies suggest that the extracellular signal-regulated kinase 1 (ERK1) MAPK signaling is involved in bradykinin-induced COX-2 expression. Bradykinin-induced ERK phosphorylation was attenuated in the cells pretreated with PKC inhibitors or transfected with PKC? siRNA. We observed the interaction between PKC? and ERK by co-immunoprecipitation experiments. These observations suggest that PKC? activation contributes to the regulation of ERK1 activation. Bradykinin stimulated the accumulation of phosphorylated ERK in the nuclear fraction, that was inhibited in the cells treated with PKC inhibitors or transfected with PKC? siRNA. Consequently, we concluded that bradykinin activates PKC? via the PLD/PDK-1 pathway, which subsequently induces activation and translocation of ERK1 into the nucleus, and contributes to COX-2 expression for prostaglandin E₂ synthesis in dermal fibroblasts.

SUBMITTER: Nakano R 

PROVIDER: S-EPMC5986758 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature