Please use this identifier to cite or link to this item: http://hdl.handle.net/10553/54586
Title: Cooperation of adenosine with macrophage toll-4 receptor agonists leads to increased glycolytic flux through the enhanced expression of PFKFB3 gene
Authors: Ruiz-García, Almudena
Monsalve, Eva
Novellasdemunt, Laura
Navarro-Sabaté, Áurea
Manzano, Anna
Rivero, Samuel
Castrillo Viguera, Antonio Jesús 
Casado, Marta
Laborda, Jorge
Bartrons, Ramón
Díaz-Guerra, María José M.
Keywords: Nf-Kappa-B
Hypoxia-Inducible Factor-1-Alpha
Activated Protein-Kinase
Tumor-Necrosis-Factor
Up-Regulation, et al
Issue Date: 2011
Publisher: 0021-9258
Journal: Journal of Biological Chemistry 
Abstract: Macrophages activated through Toll receptor triggering increase the expression of the A(2A) and A(2B) 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 A(2A) and A(2B) receptors, we demonstrate that the A(2A) receptor mediates, in part, the induction of pfkfb3 by LPS, whereas the A(2B) 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 HIF1 alpha is a key transcription factor driving pfkfb3 expression following macrophage activation by LPS, whereas synergic induction of pfkfb3 expression observed with the A(2) 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.
URI: http://hdl.handle.net/10553/54586
ISSN: 0021-9258
DOI: 10.1074/jbc.M110.190298
Source: Journal of Biological Chemistry[ISSN 0021-9258],v. 286, p. 19247-19258
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