Your browser doesn't support javascript.
loading
The lysine deacetylase inhibitor Givinostat inhibits ß-cell IL-1ß induced IL-1ß transcription and processing.
Dahllöf, Mattias S; Christensen, Dan P; Lundh, Morten; Dinarello, Charles A; Mascagni, Paolo; Grunnet, Lars G; Mandrup-Poulsen, Thomas.
Afiliación
  • Dahllöf MS; Endocrinology Research Section, Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Islets ; 4(6): 417-22, 2012.
Article en En | MEDLINE | ID: mdl-23486342
ABSTRACT

AIMS:

Pro-inflammatory cytokines and chemokines, in particular IL-1ß, IFNγ, and CXCL10, contribute to ß-cell failure and loss in DM via IL-1R, IFNγR, and TLR4 signaling. IL-1 signaling deficiency reduces diabetes incidence, islet IL-1ß secretion, and hyperglycemia in animal models of diabetes. Further, IL-1R antagonism improves normoglycemia and ß-cell function in type 2 diabetic patients. Inhibition of lysine deacetylases (KDACi) counteracts ß-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 ß-cell expression of the ß-cell toxic inflammatory molecules IL-1ß and CXCL10 induced by single cytokines.

RESULTS:

CXCL10 did not induce transcription of IL-1ß mRNA. IL-1ß induced ß-cell IL-1ß mRNA and both IL-1ß and IFNγ individually induced Cxcl10 mRNA transcription. Givinostat inhibited IL-1ß-induced IL-1ß mRNA expression in INS-1 and rat islets and IL-1ß processing in INS-1 cells. Givinostat also reduced IFNγ induced Cxcl10 transcription in INS-1 cells but not in rat islets, while IL-1ß induced Cxcl10 transcription was unaffected in both. MATERIALS AND

METHODS:

INS-1 cells and rat islets of Langerhans were exposed to IL-1ß, IFNγ or CXCL10 in the presence or absence of KDACi (givinostat). Cytokine and chemokine mRNA expressions were quantified by real-time qPCR, and IL-1ß processing by western blotting of cell lysates. CONCLUSION/

INTERPRETATION:

Inhibition of ß-cell IL-1ß expression and processing and Cxcl10 transcription contributes to the ß-cell protective actions of KDACi. In vitro ß-cell destructive effects of CXCL10 are not mediated via IL-1ß transcription. The differential proinflammatory actions of KDACs may be attractive novel drug targets in DM.
Asunto(s)
Palabras clave

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Carbamatos / Diabetes Mellitus / Células Secretoras de Insulina / Interleucina-1beta / Inhibidores de Histona Desacetilasas Límite: Animals / Humans Idioma: En Revista: Islets Asunto de la revista: ENDOCRINOLOGIA / GASTROENTEROLOGIA Año: 2012 Tipo del documento: Article País de afiliación: Dinamarca

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Carbamatos / Diabetes Mellitus / Células Secretoras de Insulina / Interleucina-1beta / Inhibidores de Histona Desacetilasas Límite: Animals / Humans Idioma: En Revista: Islets Asunto de la revista: ENDOCRINOLOGIA / GASTROENTEROLOGIA Año: 2012 Tipo del documento: Article País de afiliación: Dinamarca