Adenosine inhibits macrophage colony-stimulating factor-dependent proliferation of macrophages through the induction of p27(kip-1) expression

Jordi Xaus, Annabel F. Valledor, Marina Cardó, Laura Marquès, Jorge Beleta, José M. Palacios, Antonio Celada

Research output: Contribution to journalArticlepeer-review

69 Scopus citations

Abstract

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), A2(A) ([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 A2(B) 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 A2(B) adenosine receptor, the generation of cAMP, and the induction of p27(kip)-1 expression.

Original languageEnglish (US)
Pages (from-to)4140-4149
Number of pages10
JournalJournal of Immunology
Volume163
Issue number8
StatePublished - 1999
Externally publishedYes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Fingerprint

Dive into the research topics of 'Adenosine inhibits macrophage colony-stimulating factor-dependent proliferation of macrophages through the induction of p27(kip-1) expression'. Together they form a unique fingerprint.

Cite this