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Cooperation of adenosine with macrophage toll-4 receptor agonists leads to increased glycolytic flux through the enhanced expression of PFKFB3 gene

AuthorsRuiz-García, A.; Monsalve, E.; Novellasdemunt, L.; Navarro-Sabaté, Á.; Manzano, A.; Rivero, S.; Castrillo, A.; Casado, Marta ; Laborda, J.; Bartrons, R.; Díaz-Guerra, M.J.M.
KeywordsToll-like Receptors
Adenosine Receptor
Lipopolysaccharide (LPS)
Gene Expression
Issue Date2011
PublisherAmerican Society for Biochemistry and Molecular Biology
CitationJournal of Biological Chemistry 286: 19247-19258 (2011)
AbstractMacrophages activated through Toll receptor triggering increase the expression of the A2A and A2B adenosine receptors. In this study, we show that adenosine receptor activation enhances LPS-induced pfkfb3 expression, resulting in an increase of the key glycolytic allosteric regulator fructose 2,6-bisphosphate and the glycolytic flux. Using shRNA and differential expression of A2A and A2B receptors, we demonstrate that the A2A receptor mediates, in part, the induction of pfkfb3 by LPS, whereas the A2B receptor, with lower adenosine affinity, cooperates when high adenosine levels are present. pfkfb3 promoter sequence deletion analysis, site-directed mutagenesis, and inhibition by shRNAs demonstrated that HIF1α is a key transcription factor driving pfkfb3 expression following macrophage activation by LPS, whereas synergic induction of pfkfb3 expression observed with the A2 receptor agonists seems to depend on Sp1 activity. Furthermore, levels of phospho-AMP kinase also increase, arguing for increased PFKFB3 activity by phosphorylation in long term LPS-activated macrophages. Taken together, our results show that, in macrophages, endogenously generated adenosine cooperates with bacterial components to increase PFKFB3 isozyme activity, resulting in greater fructose 2,6-bisphosphate accumulation. This process enhances the glycolytic flux and favors ATP generation helping to develop and maintain the long term defensive and reparative functions of the macrophages. © 2011 by The American Society for Biochemistry and Molecular Biology, Inc.
Description12 páginas, 7 figuras.
Identifiersdoi: 10.1074/jbc.M110.190298
issn: 0021-9258
e-issn: 1083-351X
Appears in Collections:(IBV) Artículos
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