Protein kinase C‐ε mediates bradykinin‐induced cyclooxygenase‐2 expression in human airway smooth muscle cells

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Abstract
We previously reported that proinflammatory mediator bradykinin (BK) induces cyclooxygenase (COX)‐2 expression in human airway smooth muscle (HASM), but the mechanism is unknown in any biological system. Here, we studied the role of specific protein kinase C (PKC) isozyme(s) in COX‐2 expression. Among the eight PKC isozymes present in HASM cells, the Ca2+‐independent PKC‐δ and ‐ε and the Ca2+‐dependent PKC‐α and ‐βI were translocated to the nucleus upon BK stimulation. BK‐induced COX‐2 expression and prostaglandin E2 (PGE2) accumulation were mimicked by the direct PKC activator phorbol 12‐myristate 13‐acetate (PMA) and inhibited by the broad spectrum PKC inhibitor bisindolylmaleimide I. However, the selective Ca2+‐dependent PKC isozyme inhibitor Go 6976 had no effect. Furthermore, the membrane‐permeable calcium chelator BAPTA‐AM had no effect on BK‐induced COX‐2 expression and COX activity despite its inhibition of PGE2 accumulation, suggesting the involvement of Ca2+‐independent PKC isozymes. Rottlerin, a PKC‐δ inhibitor, also had no effect, likely implicating PKC‐ε. BK‐stimulated transcriptional activation of a COX‐2 promoter reporter construct was enhanced by overexpression of wild‐type PKC‐ε and abolished by a dominant negative PKC‐ε, but it was not affected by wild‐type or dominant negative PKC‐α or ‐δ. Collectively, our results demonstrate that PKC‐ε mediates BK‐induced COX‐2 expression in HASM cells.
Funding Information
  • Wellcome (05710)

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