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

• Published in: Journal of Immunology 2007-10, Vol.179 (8), p.4953-4957
• Main Authors: Dufort, Fay J, Bleiman, Blair F, Gumina, Maria R, Blair, Derek, Wagner, Dean J, Roberts, Mary F, Abu-Amer, Yousef, Chiles, Thomas C
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis - immunology; B-Lymphocyte Subsets - cytology; B-Lymphocyte Subsets - immunology; B-Lymphocyte Subsets - metabolism; Cell Survival - immunology; Energy Metabolism - immunology; Glucose - metabolism; Glycolysis; Interleukin-4 - physiology; Mice; Mice, Inbred BALB C; Mice, Knockout; Signal Transduction - immunology; STAT6 Transcription Factor - physiology
• ISSN: 0022-1767; 1550-6606; 1365-2567
• DOI: 10.4049/jimmunol.179.8.4953

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 p85alpha 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.