{"title":"Acting via A2 receptors, adenosine inhibits the production of tumor necrosis factor-alpha of endotoxin-stimulated human polymorphonuclear leukocytes.","authors":"M Thiel, A Chouker","doi":"","DOIUrl":null,"url":null,"abstract":"<p><p>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.</p>","PeriodicalId":23085,"journal":{"name":"The Journal of laboratory and clinical medicine","volume":"126 3","pages":"275-82"},"PeriodicalIF":0.0000,"publicationDate":"1995-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"The Journal of laboratory and clinical medicine","FirstCategoryId":"1085","ListUrlMain":"","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
引用次数: 0
Abstract
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.