Fringe controls naïve CD4(+)T cells differentiation through modulating notch signaling in asthmatic rat models.
The ability of Notch signaling to regulate T helper cell development and differentiation has been widely accepted. Fringe, O-fucose-β1,3-N-acetylglucosaminyltransferases modulate Notch receptor expression and promote the Notch signaling pathway through receptor-ligand binding. In this study, we assayed the expression levels of three Fringe homologs in naive CD4(+)T cells in asthmatic rats. We found that Radical Fringe (Rfng) was highly expressed, whereas both Lunatic Fringe (Lfng) and Manic Fringe (Mfng) were expressed at low levels. Down-regulation of Rfng using siRNA, and overexpression of Lfng or Mfng enhanced Th1 subset lineages and diminished Th2 subset lineages. Notch signaling was more activated in asthmatic naïve CD4(+)T cells than in control cells, and Lfng, but not Mfng or Rfng, partly inhibited Notch signaling in asthmatic naïve CD4(+)T lymphocytes. Lfng overexpression resulted in significantly decreased Th2 cytokine production in asthma, which was the same effect as the GSI (γ-secretase inhibitor) treatment alone, but had an increased effect on Th1 cytokines than GSI treatment. Collectively, these data identify the essential role of Fringe modulating naïve CD4(+)T cells differentiation through Notch signaling. Lfng regulated Th2 cells differentiation via a Notch-dependent manner and Th1 cells differentiation via a Notch-independent manner. Fringe could be a therapeutic strategy for the management and prevention of allergic asthma.
Department of Respiratory Medicine, Xinhua Hospital, Shanghai Jiaotong University, School of Medicine, Shanghai, China.
Wen
W
Gu
Weiguo
W
Xu
Tao
T
Ding
Xuejun
X
Guo
D000818:Animals; D001249:Asthma / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology* / Q000276:immunology / Q000378:metabolism; D002454:Cell Differentiation; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D020868:Gene Silencing; D016695:Glycosyltransferases / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D017351:N-Acetylglucosaminyltransferases / Q000378:metabolism / Q000502:physiology*; D051381:Rats; D051880:Receptors, Notch / Q000378:metabolism*; D015398:Signal Transduction; D018417:Th1 Cells / Q000378:metabolism; D018418:Th2 Cells / Q000378:metabolism
D051880:Receptors, Notch; D016695:Glycosyltransferases; C498391:Lfng protein, rat; D017351:N-Acetylglucosaminyltransferases