Acting via A2 receptors, adenosine inhibits the production of tumor necrosis factor-alpha of endotoxin-stimulated human polymorphonuclear leukocytes.
Human polymorphonuclear leukocytes (PMNLs) have recently been shown to release cytokines in response to a variety of inflammatory stimuli. Because adenosine (AR) modulates numerous functions of human PMNLs, the effect of the metabolic stable AR derivative 2-chloro-adenosine was tested on the production of tumor necrosis factor-alpha (TNF-alpha) by lipopolysaccharide-stimulated PMNLs. In addition, the highly selective A1-receptor agonist 2-chloro-N6-cyclopentyladenosine (CCPA) and the A2 receptor agonist 5'-(N-cyclopropyl)-carboxamido-adenosine (CPCA) were compared for their effects on the lipopolysaccharide-stimulated TNF-alpha production. All AR agonists inhibited the lipopolysaccharide-stimulated production of TNF-alpha in a concentration-dependent fashion. The rank order of the half-maximal inhibitory concentration (IC50) of the different agonists was as follows: IC50 (2-chloro-adenosine) approximately 10(-6) mol/L > IC50 (CCPA) approximately 5 x 10(-7) mol/L >> IC50 (CPCA) = 5 x 10(-10) mol/L. Because the A2 receptor agonist was 1000 times more effective than the A1 agonist, adenosine analogs inhibited the lipopolysaccharide-stimulated production of TNF-alpha of human PMNLs most likely via an A2 receptor site. Of note, CPCA inhibited the TNF-alpha production even when PMNLs had been stimulated by lipopolysaccharide for 2 hours previously. The potential pathophysiologic implications for patients with sepsis are discussed.
Thiel
M
M
Institute of Anesthesiology, University of Munich, Germany.
Chouker
A
A
D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology*; D004731:Endotoxins / Q000494:pharmacology*; D006801:Humans; D007700:Kinetics; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism*; D018047:Receptors, Purinergic P1 / Q000187:drug effects / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000378:metabolism
D004731:Endotoxins; D018047:Receptors, Purinergic P1; D014409:Tumor Necrosis Factor-alpha; C058394:2-chloro-N(6)cyclopentyladenosine; C024311:N-cyclopropyl adenosine-5'-carboxamide; D000241:Adenosine