Increased Notch pathway activation in Behcet's disease

Jian Qi, Yan Yang, Shengping Hou, Yanbin Qiao, Qian Wang, Hongsong Yu, Qi Zhang, Tao Cai, Aize Kijlstra, Peizeng Yang*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

27 Citations (Web of Science)

Abstract

Objective. Behcet's disease (BD) is a refractory inflammatory disorder with unknown causes. Since the Notch pathway is critically involved in the immune response, the present study was undertaken to investigate the role of this pathway in BD. Methods. Hes-1, Notch 1-4, Jagged-1, DLL-1 and DLL-4 expression, frequency of IFN-gamma and IL-17 expressing Th cells, Notch intracellular domain (NICD), phosphorylation of signal transducer and activator of transcription 3 (STAT3) and the production of IFN-gamma and IL-17 were examined by real-time PCR, flow cytometry and ELISA. Notch blockade was performed using the gamma-secretase inhibitor N-[N-(3,5-difluorophenacetyl)-1-alanyl]-S-phenylglycine t-butyl ester (DAPT). Transfection with miR-23b mimics and inhibitor was used to examine the effect of miR-23b on Notch pathway activation. Results. Active BD patients showed an increased activation of the Notch pathway in association with a higher Th17 response. Notch blockade preferentially inhibited Th17 responses. The effect of Notch blockade on the Th17 response was associated with a lower level of STAT3 phosphorylation. miR-23b was significantly decreased in CD4(+) T cells from active BD patients. CD4(+) T cells transfected with miR-23b showed a reduced expression of NICD and a reduced frequency of IL-17- and IFN-gamma-expressing T cells. Conclusion. The present study suggests that an increased activation of the Notch pathway may contribute to the pathogenesis of BD. Decreased expression of miR-23b may be involved in activation of the Notch pathway in BD. Manipulation of the Notch pathway may offer a novel therapeutic approach for BD.
Original languageEnglish
Pages (from-to)810-820
JournalRheumatology
Volume53
Issue number5
DOIs
Publication statusPublished - May 2014

Keywords

  • autoinflammatory conditions
  • Behcet's
  • ophthalmic
  • cell receptor-ligand interaction
  • signalling and activation
  • microRNA
  • cytokines and inflammatory mediators
  • inflammation
  • T cells
  • lymphocytes
  • molecular biology

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