Increased Notch pathway activation in Behçet's disease.
OBJECTIVE
Behçet'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-γ 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-γ and IL-17 were examined by real-time PCR, flow cytometry and ELISA. Notch blockade was performed using the γ-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-γ-expressing T cells.


CONCLUSIONS
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.
First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Ophthalmology, and Chongqing Eye Institute, Chongqing 400016, China. peizengycmu@126.com.
Jian
J
Qi
Yan
Y
Yang
Shengping
S
Hou
Yanbin
Y
Qiao
Qian
Q
Wang
Hongsong
H
Yu
Qi
Q
Zhang
Tao
T
Cai
Aize
A
Kijlstra
Peizeng
P
Yang
D000328:Adult; D001528:Behcet Syndrome / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology*; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism / Q000473:pathology; D016022:Case-Control Studies; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000378:metabolism; D051880:Receptors, Notch / Q000502:physiology*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D018417:Th1 Cells / Q000378:metabolism / Q000473:pathology; D058504:Th17 Cells / Q000378:metabolism / Q000473:pathology
D016207:Cytokines; C552430:MIRN23a microRNA, human; D035683:MicroRNAs; D051880:Receptors, Notch; D050796:STAT3 Transcription Factor
Behçet’s; T cells; autoinflammatory conditions; cell receptor–ligand interaction; cytokines and inflammatory mediators; inflammation; lymphocytes; microRNA; molecular biology; ophthalmic; signalling and activation