The role of adenosine receptors in regulating production of tumour necrosis factor-α and chemokines by human lung macrophages

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Abstract

Background and purpose: Adenosine is a major endogenous regulator of macrophage function, and activates four specific adenosine receptors (A 1, A 2A, A 2B and A 3). Here, we have assessed in human lung macrophages the modulation of the expression of adenosine receptor mRNA by lipopolysaccharide (LPS), and the relative contributions of the different adenosine receptors to LPS-induced production of tumour necrosis factor (TNF)-α and chemokines. Experimental approach: Lung macrophages isolated from resected lungs were stimulated with LPS and treated with adenosine receptor agonists or/and antagonists. Adenosine receptor expression was assessed with qRT-PCR. Cytokines were measured in lung macrophage supernatants with elisa. Key results: LPS increased (about 400-fold) mRNA for A 2A adenosine receptors, decreased mRNA for A 1 and A 2B, but had no effect on A 3 adenosine receptor mRNA. The adenosine receptor agonist NECA inhibited TNF-α production concentration dependently, whereas the A 1 receptor agonist, CCPA, and the A 3 receptor agonist, AB-MECA, inhibited TNF-α production only at concentrations affecting A 2A receptors. NECA also inhibited the production of CCL chemokines (CCL2, CCL3, CCL4, CCL5) and CXCL chemokines (CXCL9 and CXCL10), but not that of CXCL1, CXCL8 and CXCL5. Reversal of NECA-induced inhibition of TNF-α and chemokine production by the selective A 2A adenosine receptor antagonist ZM 241385, but not the A 2B receptor antagonist, MRS 1754, or the A 3 receptor antagonist, MRS 1220, indicated involvement of A 2A receptors. Conclusions and implications: LPS up-regulated A 2A adenosine receptor gene transcription, and this receptor subtype mediated inhibition of the LPS-induced production of TNF-α and of a subset of chemokines in human lung macrophages. © 2010 The Authors.

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Buenestado, A., Delyle, S. G., Arnould, I., Besnard, F., Naline, E., Blouquit-Laye, S., … Devillier, P. (2010). The role of adenosine receptors in regulating production of tumour necrosis factor-α and chemokines by human lung macrophages. British Journal of Pharmacology, 159(6), 1304–1311. https://doi.org/10.1111/j.1476-5381.2009.00614.x

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