Histone deacetylase 1 and 3 inhibitors alleviate colon inflammation by inhibiting Th17 cell differentiation.

Abstract

BACKGROUND:

The etiology of inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn's disease (CD), is not completely clear, but its pathogenesis is closely related to T helper 17 (Th17) cells. Several histone deacetylase (HDAC) inhibitors have been shown to exert potent anti-inflammatory effects and modulate Th17 cell polarization. Owing to the large variety and broad expression of HDACs, finding specific therapeutic targets for IBD is of clinical importance.

METHODS:

The proportions of Th17 cells and interleukin (IL)-17A produced between patients with UC and healthy volunteers were compared. The differentiation of human peripheral blood mononuclear cells (PBMCs) into Th17 cells was induced in vitro. Differentiated Th17 cells were treated with RGFP109 (RG), a selective inhibitor of HDAC1 and 3, to observe its effects on these cells. Subsequently, colitis was induced in mice and treated with RG. The proportion of Th17 cells, the severity of colitis in mice, and colon histopathology and immunohistochemistry were evaluated respectively.

RESULTS:

The proportion of Th17 cells and IL-17A production was significantly increased in patients with UC than in healthy individuals. RG inhibited the differentiation of human PBMCs into Th17 cells and reduced IL-17A secretion in vitro. RG-treated colitis mice had a lower Th17 ratio, mild colon inflammation, and decreased expression of HDAC1 and 3 in the colon.

CONCLUSIONS:

HDAC1 and 3 inhibitors can modulate the differentiation of inflammatory Th17 cells, downregulate IL-17A levels, and exert anti-inflammatory effects in experimental colitis mice, indicating that HDAC1 and 3 may be potential therapeutic targets for patients with IBD.

• Authors: Zhengrong Gu, Xiaotian Chen, Dandan Zhu, Songting Wu, Chenggong Yu
• Journal: Journal of clinical laboratory analysis (J Clin Lab Anal) Vol. 36 Issue 10 Pg. e24699 (Oct 2022) ISSN: 1098-2825 [Electronic] United States
• PMID: 36106389 (Publication Type: Journal Article)
• Copyright: © 2022 The Authors. Journal of Clinical Laboratory Analysis published by Wiley Periodicals LLC.

Chemical References

• Anti-Inflammatory Agents
• Interleukin-17
• Histone Deacetylase 1

Topics

• Animals
• Anti-Inflammatory Agents (metabolism)
• Cell Differentiation
• Colitis (drug therapy, metabolism, pathology)
• Colitis, Ulcerative (drug therapy, pathology)
• Histone Deacetylase 1 (metabolism, pharmacology)
• Humans
• Inflammation (pathology)
• Inflammatory Bowel Diseases
• Interleukin-17
• Leukocytes, Mononuclear (metabolism)
• Mice
• Th17 Cells (pathology)