Differentiation stage-specific requirement in hypoxia-inducible factor-1α–regulated glycolytic pathway during murine B cell development in bone marrow

H Kojima, A Kobayashi, D Sakurai, Y Kanno… - The journal of …, 2010 - journals.aai.org
H Kojima, A Kobayashi, D Sakurai, Y Kanno, H Hase, R Takahashi, Y Totsuka, GL Semenza…
The journal of immunology, 2010journals.aai.org
Abstract Hypoxia-inducible factor (HIF)-1α plays a central role in oxygen homeostasis and
energy supply by glycolysis in many cell types. We previously reported that an HIF-1α gene
deficiency caused abnormal B cell development and autoimmunity. In this study we show
that HIF-1α–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-1α–deficient B220+ bone marrow cells is much less functionally effective …
Abstract
Hypoxia-inducible factor (HIF)-1α plays a central role in oxygen homeostasis and energy supply by glycolysis in many cell types. We previously reported that an HIF-1α gene deficiency caused abnormal B cell development and autoimmunity. In this study we show that HIF-1α–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-1α–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-1α–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-1α–deficient cells than in wild-type cells. In agreement with these findings, HIF-1α–deficient cells used pyruvate more efficiently than wild-type cells. The key role of HIF-1α–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-1α plays an important role in B cell development.
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