The Role of Notch Signaling Pathway in Adult Patients with Epstein-Barr Virus-induced Infectious Mononucleosis
Objective:To investigate the changes of Notch signaling molecules and Th22 cells in adult patients with infectious mononucleosis(IM),and assess the regulatory function of Notch signaling inhibition to Th22 cells.Methods:Forty-two IM patients and twenty-one healthy controls were enrolled in this study.Their peripheral blood was collected,from which plasma and peripheral blood mononuclear cells(PBMCs)were isolated.Plasma interleukin(IL)-17 and IL-22 were measured by enzyme-linked immunosorbent assay.The percentages of CD3+CD4+IL-17+Th17 cells and CD3+CD4+IL-22+Th22 cells were investigated by flow cytometry.The mRNA relative levels corresponding to Th1 7 transcription factor retinoic acid related orphan receptor γt(RORγt),Th22 transcription factor aryl hydrocarbon receptor(AhR),and Notch signaling pathway molecules(including Notch receptors,Notch ligands,Notch downstream molecules)were semi-quantified by real-time PCR.CD4+T cells were purified and stimulated with γ-secretase inhibitor(GSI).Cellular proliferation,Th17 and Th22 percentage,IL-17 and IL-22 secretion,transcription factor mRNA were measured in response to GSI stimulation.Results:The relative expression levels of Notch1 and Notch2 mRNA in PBMCs of IM group were 13.58±3.18 and 4.73±1.16,respectively,which were significantly higher than 1.09± 0.12 and 1.07±0.15 in PBMCs of control group(both P＜0.001).However,there were no significant differences in relative expression levels of Notch3 and Notch4 mRNA between IM group and control group(P＞0.05).The relative expression levels of Notch ligands(including DLL1 and Jagged1)mRNA and Notch downstream molecules(including Hes1,Hes5,and Hey1)were increased in IM group compared with control group(all P＜0.001).In IM group,the Th17 and Th22 percentage were 5.03％±1.15％and 4.48％±1.29％,respectively,which were both higher than 4.36％±0.82％and 3.83％±0.55％in control group(both P＜0.05).In IM group,the IL-17 and IL-22 level were(301.1±53.82)and(101.2±16.45)pg/ml,respectively,which were both higher than(237.2±72.18)and(84.75 ±11.83)pg/ml in control group(both P＜0.001).In IM group,the relative expression levels of RORγt and AhR mRNA were 1.25±0.22 and 1.21±0.12,respectively,which were both higher than 0.99±0.15 and 1.04±0.11 in control group(both P＜0.001).There were no remarkable differences in CD4+T cell proliferation,Th17 percentage,IL-17 secretion,and relative expression level of RORγt mRNA between cells with GSI stimulation and without GSI stimulation(P＞0.05).GSI stimulation reduced Th22 percentage,IL-22 secretion,and relative expression level of AhR mRNA compared with non-stimulation(all P＜0.05).Conclusion:Notch signaling pathway regulates IL-22 secretion by CD4+T cells via AhR in IM patients.Notch-AhR-Th22 pathway may take part in the pathogenesis of IM.
NETL
NSTL
万方数据
维普
