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Am J Pathol. 2014 Apr;184(4):1085-1093. doi: 10.1016/j.ajpath.2013.12.010. Epub 2014 Feb 1.

Blockade of Notch signaling ameliorates murine collagen-induced arthritis via suppressing Th1 and Th17 cell responses.

Author information

1
Zhenjiang Key Laboratory of Medical Immunology, Department of Laboratory Medicine, Affiliated Hospital of Jiangsu University, Zhenjiang, China. Electronic address: jiaozhijun@ujs.edu.cn.
2
Department of Pathogenic Biology, School of Medical Science and Laboratory Medicine, Jiangsu University, Zhenjiang, China.
3
Zhenjiang Key Laboratory of Medical Immunology, Department of Laboratory Medicine, Affiliated Hospital of Jiangsu University, Zhenjiang, China.
4
Department of Immunology, School of Medical Science and Laboratory Medicine, Jiangsu University, Zhenjiang, China.
5
Department of Pathology and Center of Infection and Immunology, The University of Hong Kong, Hong Kong, China. Electronic address: liweilu@hku.hk.

Abstract

Recent studies have demonstrated that Notch signaling is critically involved in the regulation of immune response and contributes to autoimmune pathogenesis. Here, Notch signaling was found to be activated in CD4(+) T cells and synovial tissue from collagen-induced arthritis mice. In vivo administration of the γ-secretase inhibitor N-[N-(3,5-difluorophenacetyl-l-alanyl)]-S-phenylglycine t-butyl ester (DAPT) substantially reduced the severity of arthritic symptoms and joint damage in collagen-induced arthritis mice. Notably, DAPT treatment significantly suppressed Th1- and Th17-cell responses in spleen and lymph nodes and reduced IFN-γ and IL-17 levels in plasma. In polarization culture, DAPT treatment markedly reduced Th17 cell expansion from naïve T cells, whereas fusion protein of the Notch receptor ligand delta-like 3 significantly increased the frequency and absolute number of Th17 cells. These results suggest a novel therapeutic strategy for treatment of human rheumatoid arthritis by targeting Notch signaling using γ-secretase inhibitors.

PMID:
24492199
DOI:
10.1016/j.ajpath.2013.12.010
[Indexed for MEDLINE]
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