Butyrate inhibits IL-1ß-induced inflammatory gene expression by suppression of NF-κB activity in pancreatic beta cells.
J Biol Chem
; 298(9): 102312, 2022 09.
Article
em En
| MEDLINE
| ID: mdl-35921894
ABSTRACT
Cytokine-induced beta cell dysfunction is a hallmark of type 2 diabetes (T2D). Chronic exposure of beta cells to inflammatory cytokines affects gene expression and impairs insulin secretion. Thus, identification of anti-inflammatory factors that preserve beta cell function represents an opportunity to prevent or treat T2D. Butyrate is a gut microbial metabolite with anti-inflammatory properties for which we recently showed a role in preventing interleukin-1ß (IL-1ß)-induced beta cell dysfunction, but how prevention is accomplished is unclear. Here, we investigated the mechanisms by which butyrate exerts anti-inflammatory activity in beta cells. We exposed mouse islets and INS-1E cells to a low dose of IL-1ß and/or butyrate and measured expression of inflammatory genes and nitric oxide (NO) production. Additionally, we explored the molecular mechanisms underlying butyrate activity by dissecting the activation of the nuclear factor-κB (NF-κB) pathway. We found that butyrate suppressed IL-1ß-induced expression of inflammatory genes, such as Nos2, Cxcl1, and Ptgs2, and reduced NO production. Butyrate did not inhibit IκBα degradation nor NF-κB p65 nuclear translocation. Furthermore, butyrate did not affect binding of NF-κB p65 to target sequences in synthetic DNA but inhibited NF-κB p65 binding and RNA polymerase II recruitment to inflammatory gene promoters in the context of native DNA. We found this was concurrent with increased acetylation of NF-κB p65 and histone H4, suggesting butyrate affects NF-κB activity via inhibition of histone deacetylases. Together, our results show butyrate inhibits IL-1ß-induced inflammatory gene expression and NO production through suppression of NF-κB activation and thereby possibly preserves beta cell function.
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Base de dados:
MEDLINE
Assunto principal:
Butiratos
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Anti-Inflamatórios não Esteroides
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NF-kappa B
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Diabetes Mellitus Tipo 2
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Células Secretoras de Insulina
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Interleucina-1beta
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Inibidores de Histona Desacetilases
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Inflamação
Idioma:
En
Ano de publicação:
2022
Tipo de documento:
Article