title: Suppression of monosodium urate crystal-induced cytokine production by butyrate is mediated by the inhibition of class I histone deacetylases.
abstract: OBJECTIVE
  Acute gouty arthritis is caused by endogenously formed monosodium urate (MSU) crystals, which are potent activators of the NLRP3 inflammasome. However, to induce the release of active interleukin (IL)-1β, an additional stimulus is needed. Saturated long-chain free fatty acids (FFAs) can provide such a signal and stimulate transcription of pro-IL-1β. In contrast, the short-chain fatty acid butyrate possesses anti-inflammatory effects. One of the mechanisms involved is inhibition of histone deacetylases (HDACs). Here, we explored the effects of butyrate on MSU+FFA-induced cytokine production and its inhibition of specific HDACs.
  
  
  METHODS
  Freshly isolated peripheral blood mononuclear cells (PBMCs) from healthy donors were stimulated with MSU and palmitic acid (C16.0) in the presence or absence of butyrate or a synthetic HDAC inhibitor. Cytokine responses were measured with ELISA and quantitative PCR. HDAC activity was measured with fluorimetric assays.
  
  
  RESULTS
  Butyrate decreased C16.0+MSU-induced production of IL-1β, IL-6, IL-8 and IL-1β mRNA in PBMCs from healthy donors. Similar results were obtained in PBMCs isolated from patients with gout. Butyrate specifically inhibited class I HDACs. The HDAC inhibitor, panobinostat and the potent HDAC inhibitor, ITF-B, also decreased ex vivo C16.0+MSU-induced IL-1β production.
  
  
  CONCLUSIONS
  In agreement with the reported low inhibitory potency of butyrate, a high concentration was needed for cytokine suppression, whereas synthetic HDAC inhibitors showed potent anti-inflammatory effects at nanomolar concentrations. These novel HDAC inhibitors could be effective in the treatment of acute gout. Moreover, the use of specific HDAC inhibitors could even improve the efficacy and reduce any potential adverse effects.
authors.affiliation: Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Maartje C P
authors.initials: MC
authors.lastname: Cleophas
authors.affiliation: Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Tania O
authors.initials: TO
authors.lastname: Crişan
authors.affiliation: Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Heidi
authors.initials: H
authors.lastname: Lemmers
authors.affiliation: Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Helga
authors.initials: H
authors.lastname: Toenhake-Dijkstra
authors.affiliation: Department of Research and Development, Italfarmaco, Cinisello Balsamo, Italy.
authors.forename: Gianluca
authors.initials: G
authors.lastname: Fossati
authors.affiliation: Department of Rheumatology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Tim L
authors.initials: TL
authors.lastname: Jansen
authors.affiliation: Division of Infectious Diseases, University of Colorado School of Medicine, Aurora, Colorado, USA Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Charles A
authors.initials: CA
authors.lastname: Dinarello
authors.affiliation: Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Mihai G
authors.initials: MG
authors.lastname: Netea
authors.affiliation: Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Leo A B
authors.initials: LA
authors.lastname: Joosten
mesh_terms: D000328:Adult; D000975:Antioxidants / Q000494:pharmacology*; D015210:Arthritis, Gouty; D002087:Butyrates / Q000494:pharmacology*; D002219:Carbamates / Q000494:pharmacology; D003460:Crystallization; D016207:Cytokines / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006655:Histone Deacetylases; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D053583:Interleukin-1beta / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D016209:Interleukin-8 / Q000187:drug effects / Q000378:metabolism; D007963:Leukocytes, Mononuclear; D008297:Male; D008875:Middle Aged; D019308:Palmitic Acid / Q000494:pharmacology*; D000077767:Panobinostat; D012333:RNA, Messenger / Q000187:drug effects* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014527:Uric Acid / Q000494:pharmacology*
chemical_list: D000975:Antioxidants; D002087:Butyrates; C508606:CXCL8 protein, human; D002219:Carbamates; D016207:Cytokines; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; C508585:IL1B protein, human; C508600:IL6 protein, human; D007211:Indoles; D053583:Interleukin-1beta; D015850:Interleukin-6; D016209:Interleukin-8; D012333:RNA, Messenger; D014527:Uric Acid; D019308:Palmitic Acid; C575255:givinostat; D000077767:Panobinostat; D006655:Histone Deacetylases
keywords: Arthritis; Cytokines; Gout; Inflammation