title: Pharmacological preconditioning with adenosine A(1) receptor agonist suppresses cellular immune response by an A(2A) receptor dependent mechanism.
abstract: Under stressful conditions such as ischemia, sepsis, and severe trauma, adenosine levels are elevated and protect the tissue by interaction with G coupled receptors. In a model of peritonitis, we previously found that pharmacological preconditioning (PPC) of mice with a selective adenosine A1 receptor (A1R) agonist, 2-chloro-N(6)-cyclopentyladenosine (CCPA), induced the A2AR which reduces cytokine secretion and leukocyte recruitment. In our present study we determined whether mice PPC will moderate cellular immune response by the same mechanism. Similar to the effect on inflammation, PPC reduced the response to lymphocyte mitogens and allogeneic MLR response. The inhibitory effect of PPC on the immune response was A1R and A2AR dependent as illustrated by experiments with antagonists of these receptors and mice with knock down (KO) receptors. In MLR with PPC splenocytes we found reduced levels of pro-inflammatory cytokines (IFN-γ, IL-15, TNF-α) and elevation of IL-10, as well as elevation of regulatory T-cell. Our data indicate that PPC is able to remarkably suppress cellular immune response due to the sensitization A2AR. This effect of PPC sheds light on the protective role of adenosine in ischemic preconditioning and makes this treatment candidate for the prevention of graft rejection.
authors.affiliation: Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev, P.O.B. 653, Beer-Sheva 84105, Israel. Electronic address: naamanio@post.bgu.ac.il.
authors.forename: Oshri
authors.initials: O
authors.lastname: Naamani
authors.affiliation: Department of Nephrology, Soroka Medical University Center and Ben-Gurion University of the Negev, Beer-Sheva, Israel.
authors.forename: Cidio
authors.initials: C
authors.lastname: Chaimovitz
authors.affiliation: Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev, P.O.B. 653, Beer-Sheva 84105, Israel.
authors.forename: Amos
authors.initials: A
authors.lastname: Douvdevani
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D058907:Adenosine A1 Receptor Agonists / Q000494:pharmacology*; D058917:Adenosine A2 Receptor Antagonists / Q000494:pharmacology; D000818:Animals; D017252:CD3 Complex / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects; D003208:Concanavalin A / Q000494:pharmacology; D016207:Cytokines / Q000276:immunology; D007962:Leukocytes / Q000187:drug effects / Q000276:immunology; D007959:Lymphocyte Culture Test, Mixed; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D008934:Mitogens / Q000494:pharmacology; D043682:Receptor, Adenosine A1 / Q000235:genetics / Q000276:immunology*; D043705:Receptor, Adenosine A2A / Q000235:genetics / Q000276:immunology*; D013154:Spleen / Q000166:cytology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology
chemical_list: D058907:Adenosine A1 Receptor Agonists; D058917:Adenosine A2 Receptor Antagonists; D017252:CD3 Complex; D016207:Cytokines; D008934:Mitogens; D043682:Receptor, Adenosine A1; D043705:Receptor, Adenosine A2A; D003208:Concanavalin A; C058394:2-chloro-N(6)cyclopentyladenosine; D000241:Adenosine
keywords: Cellular activation; Cytokines; MLR; Regulatory T cells