AMPK Activation by A-769662 Controls IL-6 Expression in Inflammatory Arthritis
- PLoS One. 2015 Oct 16;10(10):e0140452. doi: 10.1371/journal.pone.0140452.
- 1. Division of Rheumatology, Allergy and Immunology, UC San Diego School of Medicine, La Jolla, California, United States of America.
- 2. INSERM, U1016, Institut Cochin, Paris, France; CNRS, UMR8104, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
- 3. Division of Rheumatology, Allergy and Immunology, UC San Diego School of Medicine, La Jolla, California, United States of America; VA San Diego Healthcare System, 3350 La Jolla Village Drive, La Jolla, California, United States of America.
Objective: 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.