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Cardiovascular Research 2002 54(1):95-104; doi:10.1016/S0008-6363(02)00228-6
© 2002 by European Society of Cardiology
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Copyright © 2002, European Society of Cardiology

Induction of iNOS expression in skeletal muscle by IL-1β and NF{kappa}B activation: an in vitro and in vivo study

Volker Adams*, Britta Nehrhoff, Ulrike Späte, Axel Linke, Paul C Schulze, Angelika Baur, Stephan Gielen, Rainer Hambrecht and Gerhard Schuler

University Leipzig–Heart Center Leipzig, Clinic of Cardiology, Leipzig, Germany

* Corresponding author. Universität Leipzig, Herzzentrum GmbH, Klinik für Innere Medizin/Kardiologie, Strümpellstrasse 39, D-04289 Leipzig, Germany. Tel.: +49-341-865-1620; fax: +49-341-865-1461 adav{at}medizin.uni-leipzig.de

Objective: The intracellular pathway and the regulation of inducible nitric oxide synthase (iNOS) expression in skeletal muscle is incompletely understood. In vitro studies, using different cell types, suggest that inflammatory cytokines are potential triggers to induce iNOS expression. Methods: To analyze intracellular pathways leading to iNOS induction, rat skeletal myoblasts were incubated with inflammatory cytokines and assessed for iNOS expression by Western blot and Griess reaction. To confirm the in vitro findings, local cytokine levels were determined in skeletal muscle biopsies of patients with chronic heart failure (CHF) and correlated with iNOS expression. Results: Nitrite accumulation in the myoblast culture supernatant or iNOS protein in the cell pellet was significantly increased after incubation with IL-1β in combination with {gamma}-IFN. Priming experiments revealed that {gamma}-IFN elevated the expression of IL-1β receptor mRNA, whereby IL-1β was able to induce iNOS expression. The cytokine-mediated iNOS induction was significantly reduced by blocking ERK1/ERK2 activation and completely abolished by the inhibition of NF{kappa}B. In skeletal muscle biopsies of CHF patients the local content of IL-1β was significantly increased as compared to healthy controls. Furthermore, a linear correlation between IL-1β content and iNOS expression in the skeletal muscle was detected. Conclusions: These data demonstrate that IL-1β, together with the priming effect of {gamma}-IFN, induces iNOS expression in skeletal muscle via activation of ERK1/ERK2 and NF{kappa}B.

KEYWORDS Heart failure; Nitric oxide; Cytokines; Signal transduction


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