TY - JOUR
T1 - Differentiation stage-specific requirement in hypoxia-inducible factor-1α-regulated glycolytic pathway during murine B cell development in bone marrow
AU - Kojima, Hidefumi
AU - Kobayashi, Ayano
AU - Sakurai, Daisuke
AU - Kanno, Yumiko
AU - Hase, Hidenori
AU - Takahashi, Riichi
AU - Totsuka, Yoshikazu
AU - Semenza, Gregg L.
AU - Sitkovsky, Michail V.
AU - Kobata, Tetsuji
PY - 2010/1/1
Y1 - 2010/1/1
N2 - 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.
AB - 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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U2 - 10.4049/jimmunol.0800167
DO - 10.4049/jimmunol.0800167
M3 - Article
C2 - 19949104
AN - SCOPUS:73949112134
SN - 0022-1767
VL - 184
SP - 154
EP - 163
JO - Journal of Immunology
JF - Journal of Immunology
IS - 1
ER -