Cytokine-stimulated nitric oxide production inhibits adenylyl cyclase and cAMP-dependent secretion in cholangiocytes

Carlo Spirlì, Luca Fabris, Elena Duner, Romina Fiorotto, Giorgio Ballardini, Tania Roskams, Nicholas F La Russo, Aurelio Sonzogni, Lajos Okolicsanyi, Mario Strazzabosco

Research output: Contribution to journalArticle

100 Citations (Scopus)

Abstract

Background & Aims: The biliary epithelium is involved both in bile production and in the inflammatory/reparative response to liver damage. Recent data indicate that inflammatory aggression to intrahepatic bile ducts results in chronic progressive cholestasis. Methods: To understand the effects of nitric oxide on cholangiocyte secretion and biliary tract pathophysiology we have investigated: (1) the effects of proinflammatory cytokines on NO production and expression of the inducible nitric oxide synthase (NOS2), (2) the effects of NO on cAMP-dependent secretory mechanisms, and (3) the immunohistochemical expression of NOS2 in a number of human chronic liver diseases. Results: Our results show that: (1) tumor necrosis factor (TNF)-α, and interferon (IFN)-γ, synergically stimulate NO production in cultured cholangiocytes through an increase in NOS2 gene and protein expression; (2) micromolar concentrations of NO inhibit forskolin-stimulated cAMP production by adenylyl cyclase (AC), cyclic adenosine monophosphate (cAMP)-dependent fluid secretion, and cAMP-dependent Cl- and HCO3- transport mediated by cystic fibrosis transmembrane conductance regulator (CFTR) and anion exchanger isoform 2, respectively; (3) cholestatic effects of NO and of proinflammatory cytokines are prevented by NOS-2 inhibitors and by agents (manganese(Ill)-tetrakis(4-benzoic acid)porphyrin [MnTBAP], urate, trolox) able to block the formation of reactive nitrogen oxide species (RNOS); (4) NOS2 expression is increased significantly in the biliary epithelium of patients with primary sclerosing cholangitis (PSC). Conclusions: Our findings show that proinflammatory cytokines stimulate the biliary epithelium to generate NO, via NOS2 induction, and that NO causes ductular cholestasis by a RNOS-mediated inhibition of AC and of cAMP-dependent HCO3- and Cl- secretory mechanisms. This pathogenetic sequence may contribute to ductal cholestasis in inflammatory cholangiopathies.

Original languageEnglish (US)
Pages (from-to)737-753
Number of pages17
JournalGastroenterology
Volume124
Issue number3
DOIs
StatePublished - Mar 1 2003

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Adenylyl Cyclases
Cyclic AMP
Nitric Oxide
Cytokines
Cholestasis
Reactive Nitrogen Species
Epithelium
Chloride-Bicarbonate Antiporters
Intrahepatic Bile Ducts
Fluids and Secretions
Cystic Fibrosis Transmembrane Conductance Regulator
Sclerosing Cholangitis
Biliary Tract
Nitric Oxide Synthase Type II
Colforsin
Manganese
Uric Acid
Aggression
Bile
Interferons

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Spirlì, C., Fabris, L., Duner, E., Fiorotto, R., Ballardini, G., Roskams, T., ... Strazzabosco, M. (2003). Cytokine-stimulated nitric oxide production inhibits adenylyl cyclase and cAMP-dependent secretion in cholangiocytes. Gastroenterology, 124(3), 737-753. https://doi.org/10.1053/gast.2003.50100

Cytokine-stimulated nitric oxide production inhibits adenylyl cyclase and cAMP-dependent secretion in cholangiocytes. / Spirlì, Carlo; Fabris, Luca; Duner, Elena; Fiorotto, Romina; Ballardini, Giorgio; Roskams, Tania; La Russo, Nicholas F; Sonzogni, Aurelio; Okolicsanyi, Lajos; Strazzabosco, Mario.

In: Gastroenterology, Vol. 124, No. 3, 01.03.2003, p. 737-753.

Research output: Contribution to journalArticle

Spirlì, C, Fabris, L, Duner, E, Fiorotto, R, Ballardini, G, Roskams, T, La Russo, NF, Sonzogni, A, Okolicsanyi, L & Strazzabosco, M 2003, 'Cytokine-stimulated nitric oxide production inhibits adenylyl cyclase and cAMP-dependent secretion in cholangiocytes', Gastroenterology, vol. 124, no. 3, pp. 737-753. https://doi.org/10.1053/gast.2003.50100
Spirlì, Carlo ; Fabris, Luca ; Duner, Elena ; Fiorotto, Romina ; Ballardini, Giorgio ; Roskams, Tania ; La Russo, Nicholas F ; Sonzogni, Aurelio ; Okolicsanyi, Lajos ; Strazzabosco, Mario. / Cytokine-stimulated nitric oxide production inhibits adenylyl cyclase and cAMP-dependent secretion in cholangiocytes. In: Gastroenterology. 2003 ; Vol. 124, No. 3. pp. 737-753.
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AU - Spirlì, Carlo

AU - Fabris, Luca

AU - Duner, Elena

AU - Fiorotto, Romina

AU - Ballardini, Giorgio

AU - Roskams, Tania

AU - La Russo, Nicholas F

AU - Sonzogni, Aurelio

AU - Okolicsanyi, Lajos

AU - Strazzabosco, Mario

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