YC-1 potentiates cAMP-induced CREB activation and nitric oxide production in alveolar macrophages

Tsong Long Hwang*, Ming Chi Tang, Liang Mou Kuo, Wen De Chang, Pei Jen Chung, Ya Wen Chang, Yao Ching Fang

*Corresponding author for this work

Research output: Contribution to journalJournal Article peer-review

13 Scopus citations


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)E 1 (a stable PGE 2 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 PGE 1- or forskolin-induced NO production and iNOS expression in NR8383 alveolar macrophages. Combination treatment with YC-1 and PGE 1 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 PGE 1-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 PGE 1 also triggered NO production and iNOS expression. In summary, YC-1 potentiates PGE 1-induced NO production and iNOS expression in alveolar macrophages through inhibition of cAMP PDE activity and activation of the cAMP/PKA/CREB signaling pathway.

Original languageEnglish
Pages (from-to)193-200
Number of pages8
JournalToxicology and Applied Pharmacology
Issue number2
StatePublished - 15 04 2012


  • Alveolar macrophage
  • Nitric oxide
  • Phosphodiesterase
  • YC-1
  • cAMP
  • cGMP


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