4.6 Article

Differentiation Stage-Specific Requirement in Hypoxia-Inducible Factor-1 alpha-Regulated Glycolytic Pathway during Murine B Cell Development in Bone Marrow

Journal

JOURNAL OF IMMUNOLOGY
Volume 184, Issue 1, Pages 154-163

Publisher

AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.0800167

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Funding

  1. Ministry of Education, Culture, Sports, Science and Technology, Japan [15790252]
  2. Seki Minato Foundation
  3. Welfied Medicinal Research Foundation
  4. Nagao Memorial Fund
  5. National Institutes of Health [R01 CA11256-01, R01 CA111985-01]
  6. NATIONAL CANCER INSTITUTE [R01CA112561, R01CA111985] Funding Source: NIH RePORTER

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Hypoxia-inducible factor (HIF)-1 alpha plays a central role in oxygen homeostasis and energy supply by glycolysis in many cell types. We previously reported that an HIF-1 alpha gene deficiency caused abnormal B cell development and autoimmunity. In this study we show that HIF-1 alpha-enabled glycolysis during B cell development is required in a developmental stage-specific manner. Supporting this conclusion are observations that the glycolytic pathway in HIF-1 alpha-deficient B220(+) bone marrow cells is much less functionally effective than in wild-type control cells. The expression of genes encoding the glucose transporters and the key glycolytic enzyme, 6-phosphofructo-2-kinase/fructose-2,6-bishosphatase 3, was greatly reduced in HIF-1 alpha-deficient cells. The compensatory adaptation to the defect of glycolysis was reflected in higher levels of expression of respiratory chain-related genes and TCA cycle-related genes in HIF-1 alpha-deficient cells than in wild-type cells. In agreement with these findings, HIF-1 alpha-deficient cells used pyruvate more efficiently than wild-type cells. The key role of HIF-1 alpha-enabled glycolysis in bone marrow B cells was also demonstrated by glucose deprivation during in vitro bone marrow cell culture and by using a glycolysis inhibitor in the bone marrow cell culture. Taken together, these findings indicate that glucose dependency differs at different B cell developmental stages and that HIF-1 alpha plays an important role in B cell development. The Journal of Immunology, 2010, 184: 154-163.

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