title: The lysine deacetylase inhibitor Givinostat inhibits β-cell IL-1β induced IL-1β transcription and processing.
abstract: OBJECTIVE
  Pro-inflammatory cytokines and chemokines, in particular IL-1β, IFNγ, and CXCL10, contribute to β-cell failure and loss in DM via IL-1R, IFNγR, and TLR4 signaling. IL-1 signaling deficiency reduces diabetes incidence, islet IL-1β secretion, and hyperglycemia in animal models of diabetes. Further, IL-1R antagonism improves normoglycemia and β-cell function in type 2 diabetic patients. Inhibition of lysine deacetylases (KDACi) counteracts β-cell toxicity induced by the combination of IL-1 and IFNγ and reduces diabetes incidence in non-obese diabetic (NOD) mice. We hypothesized that KDACi breaks an autoinflammatory circuit by differentially preventing β-cell expression of the β-cell toxic inflammatory molecules IL-1β and CXCL10 induced by single cytokines.
  
  
  RESULTS
  CXCL10 did not induce transcription of IL-1β mRNA. IL-1β induced β-cell IL-1β mRNA and both IL-1β and IFNγ individually induced Cxcl10 mRNA transcription. Givinostat inhibited IL-1β-induced IL-1β mRNA expression in INS-1 and rat islets and IL-1β processing in INS-1 cells. Givinostat also reduced IFNγ induced Cxcl10 transcription in INS-1 cells but not in rat islets, while IL-1β induced Cxcl10 transcription was unaffected in both.
  
  
  METHODS
  INS-1 cells and rat islets of Langerhans were exposed to IL-1β, IFNγ or CXCL10 in the presence or absence of KDACi (givinostat). Cytokine and chemokine mRNA expressions were quantified by real-time qPCR, and IL-1β processing by western blotting of cell lysates.
  
  
  CONCLUSIONS
  Inhibition of β-cell IL-1β expression and processing and Cxcl10 transcription contributes to the β-cell protective actions of KDACi. In vitro β-cell destructive effects of CXCL10 are not mediated via IL-1β transcription. The differential proinflammatory actions of KDACs may be attractive novel drug targets in DM.
authors.affiliation: Endocrinology Research Section, Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Mattias S
authors.initials: MS
authors.lastname: Dahllöf
authors.forename: Dan P
authors.initials: DP
authors.lastname: Christensen
authors.forename: Morten
authors.initials: M
authors.lastname: Lundh
authors.forename: Charles A
authors.initials: CA
authors.lastname: Dinarello
authors.forename: Paolo
authors.initials: P
authors.lastname: Mascagni
authors.forename: Lars G
authors.initials: LG
authors.lastname: Grunnet
authors.forename: Thomas
authors.initials: T
authors.lastname: Mandrup-Poulsen
mesh_terms: D000818:Animals; D002219:Carbamates / Q000494:pharmacology*; D054357:Chemokine CXCL10 / Q000096:biosynthesis / Q000235:genetics; D003920:Diabetes Mellitus / Q000201:enzymology / Q000235:genetics / Q000276:immunology*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology; D007371:Interferon-gamma / Q000096:biosynthesis / Q000235:genetics; D053583:Interleukin-1beta / Q000096:biosynthesis* / Q000235:genetics; D012333:RNA, Messenger / Q000737:chemistry / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D060888:Real-Time Polymerase Chain Reaction; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D002219:Carbamates; D054357:Chemokine CXCL10; C091326:Cxcl10 protein, rat; D056572:Histone Deacetylase Inhibitors; D053583:Interleukin-1beta; D012333:RNA, Messenger; C575255:givinostat; D007371:Interferon-gamma
keywords: apoptosis; chemokines; cytokines; diabetes mellitus; histone deacetylases; inflammation