title: Effects of adenosine on adhesion molecule expression and cytokine production in human PBMC depend on the receptor subtype activated.
abstract: OBJECTIVE
  Adenosine suppresses immune responses through adenosine(2A) (A(2A)) receptors, by raising intracellular cAMP. Interleukin (IL)-18 up-regulates the expression of intercellular adhesion molecule (ICAM)-1 on monocytes, leading to production of pro-inflammatory cytokines such as IL-12, interferon (IFN)-gamma and tumor necrosis factor (TNF)-alpha by human peripheral blood mononuclear cells (PBMC). We have previously demonstrated that elevation of cAMP inhibits this IL-18-induced expression of adhesion molecules. In the present study, we examined the effect of adenosine on the IL-18-induced up-regulation of ICAM-1 on human monocytes and production of IL-12, IFN-gamma and TNF-alpha by PBMC.
  
  
  METHODS
  The expression of ICAM-1 was examined by flow cytometry. IL-12, IFN-gamma and TNF-alpha were determined by ELISA assay.
  
  
  RESULTS
  Adenosine inhibited the IL-18-induced up-regulation of ICAM-1 on human monocytes and it abolished the IL-18-enhanced production of IL-12, IFN-gamma and TNF-alpha. While an A(2A) receptor antagonist reversed the action of adenosine, an A(1) or A(3) receptor antagonist enhanced them. An A(2A) receptor agonist, CGS21680, mimicked the effects of adenosine and its effects were abolished not only by the A(2A) receptor antagonist but also by A(1) or A(3) receptor agonists. Activation via A(2A) receptors resulted in elevation of cAMP in monocytes, whereas the stimulation of A(1) or A(3) receptors inhibited it, suggesting that intracellular signal transduction following ligation of A(2A) receptors might be blocked by activation of A(1) or A(3) receptors.
  
  
  CONCLUSIONS
  Adenosine differentially regulates IL-18-induced adhesion molecule expression and cytokine production through several subtypes of its receptors.
authors.affiliation: Department of Pharmacology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Science, Shikata-cho, Okayama, Japan.
authors.forename: H K
authors.initials: HK
authors.lastname: Takahashi
authors.forename: H
authors.initials: H
authors.lastname: Iwagaki
authors.forename: R
authors.initials: R
authors.lastname: Hamano
authors.forename: H
authors.initials: H
authors.lastname: Wake
authors.forename: T
authors.initials: T
authors.lastname: Kanke
authors.forename: K
authors.initials: K
authors.lastname: Liu
authors.forename: T
authors.initials: T
authors.lastname: Yoshino
authors.forename: N
authors.initials: N
authors.lastname: Tanaka
authors.forename: M
authors.initials: M
authors.lastname: Nishibori
mesh_terms: D000241:Adenosine / Q000494:pharmacology*; D058907:Adenosine A1 Receptor Agonists; D058916:Adenosine A1 Receptor Antagonists; D058908:Adenosine A2 Receptor Agonists; D058917:Adenosine A2 Receptor Antagonists; D058909:Adenosine A3 Receptor Agonists; D058918:Adenosine A3 Receptor Antagonists; D000328:Adult; D000368:Aged; D016207:Cytokines / Q000096:biosynthesis*; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism*; D007371:Interferon-gamma / Q000096:biosynthesis; D018664:Interleukin-12 / Q000096:biosynthesis; D020382:Interleukin-18 / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000187:drug effects* / Q000378:metabolism*; D043682:Receptor, Adenosine A1 / Q000378:metabolism; D043705:Receptor, Adenosine A2A / Q000378:metabolism; D043704:Receptor, Adenosine A2B / Q000378:metabolism; D043684:Receptor, Adenosine A3 / Q000378:metabolism; D018047:Receptors, Purinergic P1 / Q000145:classification / Q000187:drug effects* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D058907:Adenosine A1 Receptor Agonists; D058916:Adenosine A1 Receptor Antagonists; D058908:Adenosine A2 Receptor Agonists; D058917:Adenosine A2 Receptor Antagonists; D058909:Adenosine A3 Receptor Agonists; D058918:Adenosine A3 Receptor Antagonists; D016207:Cytokines; D020382:Interleukin-18; D043682:Receptor, Adenosine A1; D043705:Receptor, Adenosine A2A; D043704:Receptor, Adenosine A2B; D043684:Receptor, Adenosine A3; D018047:Receptors, Purinergic P1; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; D018664:Interleukin-12; D007371:Interferon-gamma; D000241:Adenosine