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Cutting Edge: IL-4-Mediated Protection of Primary B Lymphocytes from Apoptosis via Stat6-Dependent Regulation of Glycolytic Metabolism¹

Fay J. Dufort^*, Blair F. Bleiman^*, Maria R. Gumina^*, Derek Blair^*, Dean J. Wagner, Mary F. Roberts, Yousef Abu-Amer and Thomas C. Chiles^2,*

^* Department of Biology and Department of Chemistry, Boston College, Chestnut Hill, MA 02467, Departments of Orthopedic Surgery and Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO 63110; and the Naval Health Research Center, Environmental Health Effects Laboratory, Wright Patterson Air Force Base, OH 45433

IL-4 prevents the death of naive B lymphocytes through the up-regulation of antiapoptotic proteins such as Bcl-x_L. Despite studies implicating glucose utilization in growth factor-dependent survival of hemopoietic cells, the role of glucose energy metabolism in maintaining B cell viability by IL-4 is unknown. We show that IL-4 triggers glucose uptake, Glut1 expression, and glycolysis in splenic B cells; this is accompanied by increased cellular ATP. Glycolysis inhibition results in apoptosis, even in the presence of IL-4. IL-4-induced glycolysis occurs normally in B cells deficient in insulin receptor substrate-2 or the p85 subunit of PI3K and is not affected by pretreatment with PI3K or MAPK pathway inhibitors. Stat6-deficient B cells exhibit impaired IL-4-induced glycolysis. Cell-permeable, constitutively active Stat6 is effective in restoring IL-4-induced glycolysis in Stat6-deficient B cells. Therefore, besides controlling antiapoptotic proteins, IL-4 mediates B cell survival by regulating glucose energy metabolism via a Stat6-dependent pathway.

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 work was supported by U. S. Public Health Service Grants AI60896 and AI49994. The views expressed in this article are those of the authors and do not reflect the official policy or position of the Department of the Navy, the Department of Defense, or the U. S. Government.

² Address correspondence and reprint requests to Dr. Thomas C. Chiles, Department of Biology, Boston College, 414 Higgins Hall, Chestnut Hill, MA 02467. E-mail address: ChilesT{at}bc.edu

³ Abbreviations used in this paper: IRS-2, insulin receptor substrate-2; 1D-HMQC, one-dimensional heteronuclear multiple quantum correlation; 2DG, 2-deoxy-D-glucose; WT, wild type.

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