ESPEN 2012 - Late breaking abstract submission

Topic: Late Breaking Abstract

Abs n°:ESPEN12-1870

Abs Title: ADENOSINE HAS A LIVER-PROTECTIVE EFFECT; INHIBITION OF INOS INDUCTION IN HEPATOCYTES

H. Miki ^1,*Y. Tanaka ¹M. Oishi ¹K. Tokuhara ¹M. Kaibori ¹T. Okumura ^{1 2}S. Ohashi ³K. Sato ³M. Nishizawa ²A.-H. Kwon ¹

¹Kansai Medical University , Moriguchi, ²Ritsumeikan University, Kusatsu, ³ Kyoto Prefectural University, Kyoto, Japan

Rationale: Recent accumulated evidence indicates that adenosine, which is a component of purine nucleotide, has anti-inflammatory effects in a variety of organ injuries. However, the mechanisms involved in its action are obscure. In the inflamed liver, proinflammatory cytokines stimulate the induction of inducible nitric oxide synthase (iNOS). Over-production of NO by iNOS has been implicated as a factor in liver injury. In this study, we examined “proinflammatory cytokine-stimulated hepatocytes” as a simple in vitro injury model, and investigated whether adenosine influences the induction of inducible nitric oxide synthase (iNOS) gene expression and if so, what is the mechanism involved.

Methods: Rat primary cultured hepatocytes were treated with interleukin (IL)-1β in the presence or absence of adenosine. The induction of NO production and iNOS, and its signaling pathway were analyzed.

Results: Adenosine (25-100 μg/ml) inhibited the production of NO dose-dependently and reduced expressions of iNOS mRNA and protein. Adenosine had no effects on IκB degradation, but reduced the translocation of NF-κB to the nucleus. Adenosine also inhibited the upregulation of type I IL-1 receptor (IL-1RI). Experiments with iNOS promoter-luciferase constructs revealed that adenosine decreased the levels of iNOS mRNA at both promoter transactivation and mRNA stabilization steps. Adenosine decreased the expression of iNOS gene antisense-transcript, which is involved in iNOS mRNA stability.

Conclusion: These findings demonstrate that adenosine suppresses iNOS gene expression through NF-κB- and IL1RI-dependent pathways, resulting in the reduction of NO production. Adenosine may have therapeutic potential for organ injuries including liver.

Disclosure of Interest: None Declared

Keywords: adenosine, interleukin-1β, nitric oxide production, inducible nitric oxide synthase, cultured hepatocytes.