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c-Maf and JunB Mediation of Th2 Differentiation Induced by the Type 2 G Protein-Coupled Receptor (VPAC₂) for Vasoactive Intestinal Peptide¹

Julia Voice^*, Samantha Donnelly, Glenn Dorsam^*, Gregory Dolganov, Sudhir Paul and Edward J. Goetzl^2,*

^* Departments of Medicine and Microbiology/Immunology, Division of Pulmonary Medicine, Cardiovascular Research Institute, University of California Medical Center, San Francisco, CA 94143; and Departments of Pathology and Laboratory Medicine, University of Texas Health Science Center, Houston, TX 77030

Vasoactive intestinal peptide and its G protein-coupled receptors, VPAC₁ and VPAC₂, regulate critical aspects of innate and adaptive immunity. T cell VPAC₂Rs mediate changes in cytokine generation, which potently increase the Th2/Th1 ratio and consequently shift the effector responses toward allergy and inflammation. To examine mechanisms of VPAC₂ promotion of the Th2 phenotype, we analyzed controls of IL-4 transcription in CD4 T cells from T cell-targeted VPAC₂ transgenic (Tg), VPAC₂ knockout, and wild-type (WT) mice. c-maf and junB mRNA, protein, and activity were significantly up-regulated to a higher level in TCR-stimulated CD4 T cells from Tg mice compared with those from knockout and WT C57BL/6 mice. In contrast, GATA3, T-bet, and NFATc levels were identical in WT and Tg CD4 T cells. Vasoactive intestinal peptide binding to VPAC₂ on CD4 T cells specifically induces an up-regulation of the Th2-type transcription factors c-Maf and JunB, which consequently enhances IL-4 and IL-5 production, leading to a Th2-type phenotype.

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