AMPK Activation by A-769662 Controls IL-6 Expression in Inflammatory Arthritis

Abstract : AMP-activated protein kinase (AMPK) is a serine/threonine protein kinase critically involved in the regulation of cellular energy homeostasis. It is a central regulator of both lipid and glucose metabolism. Many studies have suggested that AMPK activation exert significant anti-inflammatory and immunosuppressive effects. In this study, we assessed whether targeted activation of AMPK inhibits inflammatory arthritis in vivo. METHODS: We tested the effect of A-769662, a specific AMPK agonist (60mg/kg/bid) in mouse models of antigen-induced arthritis (AIA) and passive K/BxN serum-induced arthritis. The passive K/BxN serum-induced arthritis model was also applied to AMPKα1-deficient mice. Joints were harvested and subjected to histological analysis. IL-6 expression was measured in both joint tissues and sera by ELISA. The effect of A-769662 on bone marrow derived macrophage (BMDM) response to stimulation with TLR2 and TLR4 agonists was tested in vitro. RESULTS: AMPK activation by A-769662 reduced inflammatory infiltration and joint damage in both mouse models. IL-6 expression in serum and arthritic joints was significantly decreased in A-769662-treated mice. AMPKα1 deficient mice mildly elicited an increase of clinical arthritis. IL-6 expression at both mRNA and protein levels, phosphorylation of p65 NF-κB and MAPK phosphorylation were inhibited by A-769662 in BMDMs stimulated with either TLR2 or TLR4 agonists. CONCLUSIONS: AMPK activation by specific AMPK agonist A-769662 suppressed inflammatory arthritis in mice as well as IL-6 expression in serum and arthritic joints. These data suggest that targeted activation of AMPK has a potential to be an effective therapeutic strategy for IL-6 dependent inflammatory arthritis.
Type de document :
Article dans une revue
PLoS ONE, Public Library of Science, 2015, 10 (10), pp.e0140452. 〈10.1371/journal.pone.0140452〉
Liste complète des métadonnées

Littérature citée [37 références]  Voir  Masquer  Télécharger

http://www.hal.inserm.fr/inserm-01217825
Contributeur : Mireille Bos <>
Soumis le : mardi 20 octobre 2015 - 10:31:12
Dernière modification le : jeudi 11 janvier 2018 - 06:23:10
Document(s) archivé(s) le : vendredi 28 avril 2017 - 07:52:13

Fichier

journal.pone.0140452.pdf
Fichiers éditeurs autorisés sur une archive ouverte

Identifiants

Collections

Citation

Monica Guma, Yun Wang, Benoit Viollet, Ru Liu-Bryan. AMPK Activation by A-769662 Controls IL-6 Expression in Inflammatory Arthritis. PLoS ONE, Public Library of Science, 2015, 10 (10), pp.e0140452. 〈10.1371/journal.pone.0140452〉. 〈inserm-01217825〉

Partager

Métriques

Consultations de la notice

170

Téléchargements de fichiers

207