title: AMPK Activation by A-769662 Controls IL-6 Expression in Inflammatory Arthritis.
abstract: 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.
authors.affiliation: Division of Rheumatology, Allergy and Immunology, UC San Diego School of Medicine, La Jolla, California, United States of America.
authors.forename: Monica
authors.initials: M
authors.lastname: Guma
authors.affiliation: Division of Rheumatology, Allergy and Immunology, UC San Diego School of Medicine, La Jolla, California, United States of America.
authors.forename: Yun
authors.initials: Y
authors.lastname: Wang
authors.affiliation: INSERM, U1016, Institut Cochin, Paris, France; CNRS, UMR8104, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Benoit
authors.initials: B
authors.lastname: Viollet
authors.affiliation: 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.
authors.forename: Ru
authors.initials: R
authors.lastname: Liu-Bryan
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000172:deficiency / Q000378:metabolism*; D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000201:enzymology / Q000276:immunology / Q000378:metabolism*; D001713:Biphenyl Compounds; D001854:Bone Marrow Cells / Q000166:cytology; D004789:Enzyme Activation / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects*; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism*; D007596:Joints / Q000187:drug effects; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D011753:Pyrones / Q000494:pharmacology* / Q000627:therapeutic use; D013876:Thiophenes / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D001713:Biphenyl Compounds; D015850:Interleukin-6; D011753:Pyrones; D013876:Thiophenes; C548179:Prkaa1 protein, mouse; D055372:AMP-Activated Protein Kinases; C512408:4-hydroxy-3-(4-(2-hydroxyphenyl)phenyl)-6-oxo-7H-thieno(2,3-b)pyridine-5-carbonitrile