A selective adenosine A2A receptor agonist, ATL-146e, prevents concanavalin A-induced acute liver injury in mice.
OBJECTIVE
Concanavalin A (Con A) activates T lymphocytes and induces CD4+ T cell-mediated hepatic injury in mice. Pro-inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma), and interleukin-6 (IL-6), are critical mediators in this experimental model. Activation of adenosine A2A receptors reduces the production of various pro-inflammatory cytokines and suppresses T cell activation. A selective adenosine A2A receptor agonist (ATL-146e) has been shown to be a potent inhibitor of inflammation by increasing intracellular cyclic AMP (cAMP) in leukocytes. The aim of the present study was to determine whether ATL-146e could ameliorate Con A-induced hepatic injury, reduction of pro-inflammatory cytokine production.


METHODS
Balb/c mice were injected with 25mg/kg Con A with or without a single injection of ATL-146e (0.5-50 microg/kg), 5 min prior to Con A administration. Liver enzymes, histology, and serum levels of tumor necrosis factor-alpha, interferon-gamma, and interleukin-6 were examined. We also assessed the effects of ATL-146e on pro-inflammatory cytokine production with CD4+ T cell.


RESULTS
Pretreatment with ATL-146e significantly reduced serum levels of liver enzymes (P<0.001). The serum pro-inflammatory cytokines were all increased after Con A administration and reduced to near normal levels by ATL-146e. ATL-146e also inhibited CD4+ T cell pro-inflammatory cytokine production.


CONCLUSIONS
A selective adenosine A2A receptor agonist, ATL-146e, can prevent concanavalin A-induced hepatic injury that is presumably mediated by its anti-inflammatory properties.
Odashima
Masaru
M
Department of Gastroenterology, Akita University School of Medicine, Akita, Japan. odashima@doc.med.akita-u.ac.jp
Otaka
Michiro
M
Jin
Mario
M
Horikawa
Youhei
Y
Matsuhashi
Tamotsu
T
Ohba
Reina
R
Linden
Joel
J
Watanabe
Sumio
S
D058908:Adenosine A2 Receptor Agonists; D000818:Animals; D003208:Concanavalin A; D003509:Cyclohexanecarboxylic Acids / Q000494:pharmacology*; D007371:Interferon-gamma / Q000037:antagonists & inhibitors; D017114:Liver Failure, Acute / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D011687:Purines / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors; D000093242:Interleukin-6 Inhibitors
D058908:Adenosine A2 Receptor Agonists; D003208:Concanavalin A; D003509:Cyclohexanecarboxylic Acids; D007371:Interferon-gamma; D011687:Purines; D014409:Tumor Necrosis Factor-alpha; D000093242:Interleukin-6 Inhibitors; C431129:ATL 146e