TY - JOUR
T1 - Adenosine inhibits macrophage colony-stimulating factor-dependent proliferation of macrophages through the induction of p27(kip-1) expression
AU - Xaus, Jordi
AU - Valledor, Annabel F.
AU - Cardó, Marina
AU - Marquès, Laura
AU - Beleta, Jorge
AU - Palacios, José M.
AU - Celada, Antonio
PY - 1999
Y1 - 1999
N2 - 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.
AB - 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.
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U2 - 10.4049/jimmunol.163.8.4140
DO - 10.4049/jimmunol.163.8.4140
M3 - Article
C2 - 10510349
AN - SCOPUS:0032853298
SN - 0022-1767
VL - 163
SP - 4140
EP - 4149
JO - Journal of Immunology
JF - Journal of Immunology
IS - 8
ER -