Rac and protein kinase C-δ regulate ERKs and cytosolic phospholipase A2 in FcεRI signaling to cysteinyl leukotriene synthesis in mast cells

Sung Hoon Cho, Hye Jin You, Chang Hoon Woo, Yung Joon Yoo, Jae-Hong Kim

Research output: Contribution to journalArticle

38 Citations (Scopus)

Abstract

Although cysteinyl leukotrienes (cysLTs) are known to be principal inflammatory lipid mediators released from IgE-stimulated mast cells, the signaling mechanisms involved in the synthesis of cysLTs remain largely unknown. In the present study, therefore, we investigated the signaling pathway by which IgE induces cysLTs synthesis after binding to its high affinity receptor (FcεRI) in RBL-2H3 mast cells. We found that IgE-induced cysLT synthesis is completely abolished in RBL-2H3Rac-N17 cell, a stable cell line expressing RacN17, a dominant negative Rac1 mutant; conversely, synthesis was enhanced in cells expressing RacV12, a constitutively active Rac1 mutant, suggesting that Rac1 is a key mediator of IgE signaling to cysLT synthesis. Further analysis aimed at identifying mediators downstream of Rac1 revealed that pretreating cells with a protein kinase C-δ (PKC-δ) inhibitor or infection with an adenoviral vector harboring a dominant negative PKC-δ mutant significantly attenuates IgE-induced ERKs phosphorylation, cytosolic phospholipase A2 phosphorylation/ translocation, and cysLT synthesis. In addition, the expression of Rac N17 blocked PKC-δ translocation and impaired the phosphorylation of ERKs and cytosolic phospholipase A2 otherwise elicited by IgE stimulation. Taken together these results suggest that PKC-δ also plays a critical mediatory role in the IgE signaling pathway leading to cysLT synthesis, acting downstream of Rac1. Finally, the physiological significance of PKC-δ in the IgE signaling pathway was demonstrated in an Ag (OVA)-challenged in vivo mouse model, in which induced levels of cysLTs and airway responsiveness in lung airways were significantly diminished by prior i.p. injection of a PKC-δ inhibitor.

Original languageEnglish
Pages (from-to)624-631
Number of pages8
JournalJournal of Immunology
Volume173
Issue number1
Publication statusPublished - 2004 Jul 1

ASJC Scopus subject areas

  • Immunology

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