M1 and M2 macrophages are the key players in innate immunity, and are associated with tissue homeostasis and diseases. Although M2 macrophages are known to depend on fatty acid oxidation (FAO) for their activation, how metabolic pathways affect the production of each cytokine induced by pathogen or bacterial components is unclear. Here, we examined the role of the glycolytic pathway in M2 polarized human macrophages in cytokine production induced by lipopolysaccharide (LPS) stimulation. Human monocytes were isolated from peripheral blood by positive selection for CD14 expression and cultured with macrophage colony-stimulating factor (M-CSF), to obtain M-CSF-induced macrophages (M-MΦ). LPS-induced cytokine production by M-MΦ in the presence or absence of metabolic inhibitors was evaluated. M-MΦ showed a M2 macrophage phenotype with a high IL-10 production level. Glycolytic pathway inhibitors reduced IL-6 production by M-MΦ. Meanwhile, an FAO inhibitor suppressed IL-10 production, while it did not suppress IL-6 production. Interestingly, glycolytic pathway inhibitors downregulated extracellular signal-regulated kinase (ERK) phosphorylation, but FAO inhibitor did not. Nuclear factor kappa B (NF-κB) and the other mitogen-activated protein kinases (MAPKs), p38 and c-jun N-terminal kinase (JNK), were not affected by these metabolic inhibitors. These results suggest that M2 polarized human macrophages use the glycolytic pathway in addition to FAO for cytokine production. Furthermore, ERK may be the key molecule that links metabolic pathways to cytokine production, especially the glycolytic pathway.
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