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

Background and purpose:  Adenosine is a major endogenous regulator of macrophage function, and activates four specific adenosine receptors (A₁, A_2A, A_2B and A₃). 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 A₁ and A_2B, but had no effect on A₃ adenosine receptor mRNA. The adenosine receptor agonist NECA inhibited TNF‐α production concentration dependently, whereas the A₁ receptor agonist, CCPA, and the A₃ 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 A₃ 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.

DOI: 10.1111/j.1476-5381.2009.00614.x

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