PMID- 25362043 OWN - NLM STAT- MEDLINE DCOM- 20160406 LR - 20220316 IS - 1468-2060 (Electronic) IS - 0003-4967 (Print) IS - 0003-4967 (Linking) VI - 75 IP - 1 DP - 2016 Jan TI - AMP-activated protein kinase suppresses urate crystal-induced inflammation and transduces colchicine effects in macrophages. PG - 286-94 LID - 10.1136/annrheumdis-2014-206074 [doi] AB - OBJECTIVE: AMP-activated protein kinase (AMPK) is metabolic biosensor with anti-inflammatory activities. Gout is commonly associated with excesses in soluble urate and in nutrition, both of which suppress tissue AMPK activity. Gout is driven by macrophage-mediated inflammation transduced partly by NLRP3 inflammasome activation and interleukin (IL)-1beta release. Hence, we tested the hypothesis that AMPK activation limits monosodium urate (MSU) crystal-induced inflammation. METHODS: We studied bone marrow-derived macrophages (BMDMs) from AMPKalpha1 knockout and wild-type mice, and assessed the selective AMPK pharmacological activator A-769662 and a low concentration (10 nM) of colchicine. We examined phosphorylation (activation) of AMPKalpha Thr172, NLRP3 mRNA expression, and caspase-1 cleavage and IL-1beta maturation using western blot and quantitative RT-PCR approaches. We also assessed subcutaneous murine air pouch inflammatory responses to MSU crystals in vivo. RESULTS: MSU crystals suppressed phosphorylation of AMPKalpha in BMDMs. Knockout of AMPKalpha1 enhanced, and, conversely, A-769662-inhibited MSU crystal-induced inflammatory responses including IL-1beta and CXCL1 release in vitro and in vivo. A-769662 promoted AMPK-dependent macrophage anti-inflammatory M2 polarisation and inhibited NLRP3 gene expression, activation of caspase-1 and IL-1beta. Colchicine, at low concentration (10 nM) achieved in gout flare prophylaxis dosing, promoted phosphorylation of AMPKalpha and macrophage M2 polarisation, and reduced activation of caspase-1 and release of IL-1beta and CXCL1 by MSU crystals in BMDMs in vitro. CONCLUSIONS: AMPK activity limits MSU crystal inflammation in vitro and in vivo, and transduces multiple anti-inflammatory effects of colchicine in macrophages. Targeting increased and sustained AMPK activation in inflammatory cells merits further investigation for enhancing efficacy of prophylaxis and treatment of gouty inflammation. CI - Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/ FAU - Wang, Yun AU - Wang Y AD - Depatment of Medicine, UCSD, San Diego, California, USA. FAU - Viollet, Benoit AU - Viollet B AD - INSERM, U1016, Institut Cochin, Paris, France CNRS, UMR8104, Paris, France Universite Paris Descartes, Sorbonne Paris Cite, Paris, France. FAU - Terkeltaub, Robert AU - Terkeltaub R AD - Depatment of Medicine, UCSD, San Diego, California, USA VA San Diego Medical Center, San Diego, California, USA. FAU - Liu-Bryan, Ru AU - Liu-Bryan R AD - Depatment of Medicine, UCSD, San Diego, California, USA VA San Diego Medical Center, San Diego, California, USA. LA - eng GR - T32 AR06419/AR/NIAMS NIH HHS/United States GR - I01 BX002234/BX/BLRD VA/United States GR - R01 AI081881/AI/NIAID NIH HHS/United States GR - T32 AR064194/AR/NIAMS NIH HHS/United States GR - PAG07996/PHS HHS/United States GR - P01 AG007996/AG/NIA NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20141031 PL - England TA - Ann Rheum Dis JT - Annals of the rheumatic diseases JID - 0372355 RN - 0 (Biphenyl Compounds) RN - 0 (Gout Suppressants) RN - 0 (Pyrones) RN - 0 (Thiophenes) RN - 268B43MJ25 (Uric Acid) RN - EC 2.7.11.1 (AMPK alpha1 subunit, mouse) RN - EC 2.7.11.31 (AMP-Activated Protein Kinases) RN - P68477CD2C (4-hydroxy-3-(4-(2-hydroxyphenyl)phenyl)-6-oxo-7H-thieno(2,3-b)pyridine-5-carbonitrile) RN - SML2Y3J35T (Colchicine) SB - IM MH - AMP-Activated Protein Kinases/deficiency/drug effects/*physiology MH - Animals MH - Biphenyl Compounds MH - Cells, Cultured MH - Colchicine/*pharmacology MH - Enzyme Activation/drug effects MH - Gout/chemically induced/*enzymology/pathology MH - Gout Suppressants/*pharmacology MH - Macrophages/*drug effects/physiology MH - Mice, Knockout MH - Phosphorylation/drug effects MH - Pyrones/pharmacology MH - Thiophenes/pharmacology MH - Uric Acid PMC - PMC4417082 MID - NIHMS640981 EDAT- 2014/11/02 06:00 MHDA- 2016/04/07 06:00 PMCR- 2016/01/01 CRDT- 2014/11/02 06:00 PHST- 2014/06/10 00:00 [received] PHST- 2014/10/12 00:00 [accepted] PHST- 2014/11/02 06:00 [entrez] PHST- 2014/11/02 06:00 [pubmed] PHST- 2016/04/07 06:00 [medline] PHST- 2016/01/01 00:00 [pmc-release] AID - annrheumdis-2014-206074 [pii] AID - 10.1136/annrheumdis-2014-206074 [doi] PST - ppublish SO - Ann Rheum Dis. 2016 Jan;75(1):286-94. doi: 10.1136/annrheumdis-2014-206074. Epub 2014 Oct 31.