期刊
ELIFE
卷 3, 期 -, 页码 -出版社
ELIFE SCIENCES PUBLICATIONS LTD
DOI: 10.7554/eLife.04631
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- NCI NIH HHS [T32 CA079443] Funding Source: Medline
- NIAID NIH HHS [P01 AI054904] Funding Source: Medline
Epigenetic modifiers are an emerging class of anti-tumor drugs, potent in multiple cancer contexts. Their effect on spontaneously developing autoimmune diseases has been little explored. We report that a short treatment with I-BET151, a small-molecule inhibitor of a family of bromodomain-containing transcriptional regulators, irreversibly suppressed development of type-1 diabetes in NOD mice. The inhibitor could prevent or clear insulitis, but had minimal influence on the transcriptomes of infiltrating and circulating T cells. Rather, it induced pancreatic macrophages to adopt an anti-inflammatory phenotype, impacting the NF-kappa B pathway in particular. I-BET151 also elicited regeneration of islet beta-cells, inducing proliferation and expression of genes encoding transcription factors key to beta-cell differentiation/function. The effect on beta cells did not require T cell infiltration of the islets. Thus, treatment with I-BET151 achieves a combination therapy, currently advocated by many diabetes investigators, operating by a novel mechanism that coincidentally dampens islet inflammation and enhances beta-cell regeneration.
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