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Rac and Protein Kinase C- Regulate ERKs and Cytosolic Phospholipase A₂ in FcRI Signaling to Cysteinyl Leukotriene Synthesis in Mast Cells¹

Sung-Hoon Cho^*,, Hye-Jin You^*,, Chang-Hoon Woo^*, Yung-Joon Yoo and Jae-Hong Kim^2,*

^* School of Life Sciences and Biotechnology, Korea University, Seoul, Korea; and Department of Life Science, Gwangju Institute of Science and Technology, Gwangju, Korea

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 (FcRI) in RBL-2H3 mast cells. We found that IgE-induced cysLT synthesis is completely abolished in RBL-2H3^Rac-N17 cells, a stable cell line expressing Rac^N17, a dominant negative Rac1 mutant; conversely, synthesis was enhanced in cells expressing Rac^V12, 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- (PKC-) inhibitor or infection with an adenoviral vector harboring a dominant negative PKC- mutant significantly attenuates IgE-induced ERKs phosphorylation, cytosolic phospholipase A₂ phosphorylation/translocation, and cysLT synthesis. In addition, the expression of Rac^N17 blocked PKC- translocation and impaired the phosphorylation of ERKs and cytosolic phospholipase A₂ otherwise elicited by IgE stimulation. Taken together these results suggest that PKC- 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- 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- inhibitor.

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