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Elevating Calcium in Th2 Cells Activates Multiple Pathways to Induce IL-4 Transcription and mRNA Stabilization¹

Liying Guo^2,*, Joseph F. Urban, Jinfang Zhu^* and William E. Paul^*

^* Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892; and Nutrient Requirements & Functions Laboratory, Beltsville Human Nutrition Research Center, Agricultural Research Service, United States Department of Agriculture, Beltsville, MD 20705

PMA and ionomycin cause T cell cytokine production. We report that ionomycin alone induces IL-4 and IFN-, but not IL-2, from in vivo- and in vitro-generated murine Th2 and Th1 cells. Ionomycin-induced cytokine production requires NFAT, p38, and calmodulin-dependent kinase IV (CaMKIV). Ionomycin induces p38 phosphorylation through a calcium-dependent, cyclosporine A-inhibitable pathway. Knocking down ASK1 inhibits ionomycin-induced p38 phosphorylation and IL-4 production. Ionomycin also activates CaMKIV, which, together with p38, induces AP-1. Cooperation between AP-1 and NFAT leads to Il4 gene transcription. p38 also regulates IL-4 production by mRNA stabilization. TCR stimulation also phosphorylates p38, partially through the calcium-dependent pathway; activated p38 is required for optimal IL-4 and IFN-.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This research was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases.

² Address correspondence and reprint requests to Dr. Liying Guo, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Building 10, Room 11N322, 10 Center Drive–MSC 1892, Bethesda, MD 20892-1892. E-mail address: lguo{at}niaid.nih.gov

³ Abbreviations used in this paper: [Ca²⁺]_i, intracellular Ca²⁺ concentration; ARE, adenylate/uridylate-rich elements; CsA, cyclosporine A; LN, lymph node; MFI, mean fluorescence intensity; PB, plate-bound; PKC, protein kinase C; qPCR, quantitative PCR; shRNA, small hairpin RNA; TG, thapsigargin; UTR, untranslated region.