title: YC-1 potentiates cAMP-induced CREB activation and nitric oxide production in alveolar macrophages.
abstract: Alveolar macrophages play significant roles in the pathogenesis of several inflammatory lung diseases. Increases in exhaled nitric oxide (NO) are well documented to reflect disease severity in the airway. In this study, we investigated the effect of 3-(5'-hydroxymethyl-2'-furyl)-1-benzyl indazole (YC-1), a known activator of soluble guanylyl cyclase, on prostaglandin (PG)E₁ (a stable PGE₂ analogue) and forskolin (a adenylate cyclase activator) induced NO production and inducible NO synthase (iNOS) expression in rat alveolar macrophages (NR8383). YC-1 did not directly cause NO production or iNOS expression, but drastically potentiated PGE₁- or forskolin-induced NO production and iNOS expression in NR8383 alveolar macrophages. Combination treatment with YC-1 and PGE₁ significantly increased phosphorylation of the cAMP response element-binding protein (CREB), but not nuclear factor (NF)-κB activation. The combined effect on NO production, iNOS expression, and CREB phosphorylation was reversed by a protein kinase (PK)A inhibitor (H89), suggesting that the potentiating functions were mediated through a cAMP/PKA signaling pathway. Consistent with this, cAMP analogues, but not the cGMP analogue, caused NO release, iNOS expression, and CREB activation. YC-1 treatment induced an increase in PGE₁-induced cAMP formation, which occurred through the inhibition of cAMP-specific phosphodiesterase (PDE) activity. Furthermore, the combination of rolipram (an inhibitor of PDE4), but not milronone (an inhibitor of PDE3), and PGE₁ also triggered NO production and iNOS expression. In summary, YC-1 potentiates PGE₁-induced NO production and iNOS expression in alveolar macrophages through inhibition of cAMP PDE activity and activation of the cAMP/PKA/CREB signaling pathway.
authors.affiliation: Graduate Institute of Natural Products, College of Medicine, Chang Gung University, Taoyuan, Taiwan. htl@mail.cgu.edu.tw
authors.forename: Tsong-Long
authors.initials: TL
authors.lastname: Hwang
authors.forename: Ming-Chi
authors.initials: MC
authors.lastname: Tang
authors.forename: Liang-Mou
authors.initials: LM
authors.lastname: Kuo
authors.forename: Wen-De
authors.initials: WD
authors.lastname: Chang
authors.forename: Pei-Jen
authors.initials: PJ
authors.lastname: Chung
authors.forename: Ya-Wen
authors.initials: YW
authors.lastname: Chang
authors.forename: Yao-Ching
authors.initials: YC
authors.lastname: Fang
mesh_terms: D000818:Animals; D005576:Colforsin / Q000494:pharmacology; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D015232:Dinoprostone / Q000494:pharmacology; D020536:Enzyme Activators / Q000494:pharmacology*; D006162:Guanylate Cyclase / Q000378:metabolism; D015151:Immunoblotting; D007191:Indazoles / Q000494:pharmacology*; D007546:Isoquinolines / Q000494:pharmacology; D008171:Lung Diseases / Q000276:immunology*; D016676:Macrophages, Alveolar / Q000187:drug effects* / Q000378:metabolism; D009569:Nitric Oxide / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis / Q000378:metabolism; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D000071756:Soluble Guanylyl Cyclase; D013449:Sulfonamides / Q000494:pharmacology
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D020536:Enzyme Activators; D007191:Indazoles; D007546:Isoquinolines; D018160:Receptors, Cytoplasmic and Nuclear; D013449:Sulfonamides; C090937:3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole; D005576:Colforsin; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; D017868:Cyclic AMP-Dependent Protein Kinases; D010727:Phosphoric Diester Hydrolases; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase; D015232:Dinoprostone; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide