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Adenosine Inhibits Macrophage Colony-Stimulating Factor-Dependent Proliferation of Macrophages Through the Induction of p27^kip-1 Expression¹

Jordi Xaus^2,*, Annabel F. Valledor^2,*, Marina Cardó^*, Laura Marquès^*, Jorge Beleta, José M. Palacios and Antonio Celada^3,*

^* Departamento de Fisiologia (Biologia del Macrófag), Facultat de Biologia and Fundació August Pi i Sunyer, Campus de Bellvitge, Universitat de Barcelona, Barcelona, Spain; and Laboratorios Almirall Prodesfarma SA, Research Center, Barcelona, Spain

Adenosine is produced during inflammation and modulates different functional activities in macrophages. In murine bone marrow-derived macrophages, adenosine inhibits M-CSF-dependent proliferation with an IC₅₀ of 45 µM. Only specific agonists that can activate A_2B adenosine receptors such as 5'-N-ethylcarboxamidoadenosine, but not those active on A₁ (N⁶-(R)-phenylisopropyladenosine), A_2A ([p-(2-carbonylethyl)phenylethylamino]-5'-N-ethylcarboxamidoadenosine), or A₃ (N⁶-(3-iodobenzyl)adenosine-5'-N-methyluronamide) receptors, induce the generation of cAMP and modulate macrophage proliferation. This suggests that adenosine regulates macrophage proliferation by interacting with the A_2B receptor and subsequently inducing the production of cAMP. In fact, both 8-Br-cAMP (IC₅₀ 85 µM) and forskolin (IC₅₀ 7 µM) inhibit macrophage proliferation. Moreover, the inhibition of adenylyl cyclase and protein kinase A blocks the inhibitory effect of adenosine and its analogues on macrophage proliferation. Adenosine causes an arrest of macrophages at the G₁ phase of the cell cycle without altering the activation of the extracellular-regulated protein kinase pathway. The treatment of macrophages with adenosine induces the expression of p27^kip-1, a G₁ cyclin-dependent kinase inhibitor, in a protein kinase A-dependent way. Moreover, the involvement of p27^kip-1 in the adenosine inhibition of macrophage proliferation was confirmed using macrophages from mice with a disrupted p27^kip-1 gene. These results demonstrate that adenosine inhibits macrophage proliferation through a mechanism that involves binding to A_2B adenosine receptor, the generation of cAMP, and the induction of p27^kip-1 expression.

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