An agonist of adenosine A3 receptors decreases interleukin-12 and interferon-gamma production and prevents lethality in endotoxemic mice.
We have recently observed that the selective adenosine A3 receptor agonist N6-(3-iodobenzyl)-adenosine-5'-N-methyluronamide (IB-MECA) augments interleukin-10 and inhibits tumor necrosis factor-alpha production in endotoxemic mice. In the present study, we extended our investigations into the effect of this compound on the bacterial lipopolysaccharide (endotoxin)-induced inflammatory response in the BALB/c, as well as in the C57BL/6 interleukin-10+/+ and the interleukin-10 deficient C57BL/6 interleukin-10(0)/0 mice strains. In the BALB/c mice, i.p. pre-treatment with IB-MECA (0.2 and 0.5 mg/kg) decreased lipopolysaccharide (60 mg/kg i.p.)-induced plasma levels of interleukin-12 (p40 and p70), interferon-gamma, and nitrite/nitrate (breakdown products of nitric oxide (NO)). On the other hand, pre-treatment with this compound failed to influence lipopolysaccharide-induced plasma interleukin-1 alpha, interleukin-6, and corticosterone concentrations. Similar to its effect in BALB/c mice, IB-MECA enhanced the release of interleukin-10 in the C57BL/6 interleukin-10+/+ mice. Furthermore, IB-MECA inhibited the production of interleukin-12, interferon-gamma, and NO in both the C57BL/6 interleukin-10+/+ and C57BL/6 interleukin-10(0)/0 mice, suggesting that the inhibition of pro-inflammatory cytokine production by this compound is independent of the increased release of interleukin-10. Finally, pre-treatment with this compound protected mice against lipopolysaccharide (60 mg/kg i.p.)-induced lethality. These results indicate that stimulation of adenosine A3 receptors has potent anti-inflammatory effects and may represent a potential strategy in the treatment of septic shock and other inflammatory diseases.
Haskó
G
G
Inotek, Cincinnati, OH 45219-2374, USA.
Németh
Z H
ZH
Vizi
E S
ES
Salzman
A L
AL
Szabó
C
C
D000241:Adenosine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D003345:Corticosterone / Q000097:blood; D019446:Endotoxemia / Q000097:blood / Q000401:mortality / Q000517:prevention & control*; D004731:Endotoxins / Q000494:pharmacology; D007371:Interferon-gamma / Q000097:blood / Q000187:drug effects*; D007375:Interleukin-1 / Q000097:blood; D016753:Interleukin-10 / Q000097:blood / Q000235:genetics; D018664:Interleukin-12 / Q000097:blood*; D015850:Interleukin-6 / Q000097:blood; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009566:Nitrates / Q000097:blood; D009573:Nitrites / Q000097:blood; D011135:Polysaccharides, Bacterial / Q000494:pharmacology; D058906:Purinergic P1 Receptor Agonists; D043684:Receptor, Adenosine A3; D013045:Species Specificity; D016019:Survival Analysis
D004731:Endotoxins; D007375:Interleukin-1; D015850:Interleukin-6; D009566:Nitrates; D009573:Nitrites; D011135:Polysaccharides, Bacterial; D058906:Purinergic P1 Receptor Agonists; D043684:Receptor, Adenosine A3; D016753:Interleukin-10; C084956:N(6)-(3-iodobenzyl)-5'-N-methylcarboxamidoadenosine; D018664:Interleukin-12; D007371:Interferon-gamma; D000241:Adenosine; D003345:Corticosterone