The lysine deacetylase inhibitor Givinostat inhibits ß-cell IL-1ß induced IL-1ß transcription and processing.
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 ANDMETHODS:
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.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