摘要
Aberrant expression of CXCR4 has been indicated to play a role in the pathogenesis of systemic lupus erythematosus(SLE),but the mechanism of CXCR4 dysregulation in SLE is unclear.This study is aimed to explore the clinical significance and possible mechanisms of abnormal CXCR4 expression on B cells from patients with untreated SLE.Expression of CXCR4 on peripheral B cells was determined by flow cytometry and western blotting.Freshly isolated B cells were cultured with exogenous interleukin 21(IL-21)in the presence or absence of CD40 ligand(CD40L)plus anti-IgM antibody(aIgM),and changes in CXCR4 expression were detected.Involvement of phosphatidylinositol 3 kinase(PI3K)/Akt and Janus kinase/Signal transducer and activator of transcription(JAK/STAT)signaling pathways was assessed by adding blocking agents Ly294002 and AG490.Since CD63 is reported to mediate endosomal recruitment of CXCR4 and BCL6 is capable of silencing CD63 gene transcription,we also measured BCL6 and CD63 gene transcription with real-time PCR.It was shown that CXCR4 expression on B cells was significantly upregulated in SLE patients,especially in those with lupus nephritis,and was positively correlated with SLE Disease Activity Index scores and negatively with the serum complement 3 levels(Po0.05).Downregulation of CXCR4 by IL-21 was intact.In contrast,a similar effect of aIgM plus CD40L in downregulating CXCR4 expression was defective in SLE patients but was restored by co-stimulation with IL-21 in vitro.Both Ly294002 and AG490 promoted downregulation of surface CXCR4 expression on B cells from SLE patients(P=0.078 and P=0.064).Furthermore,B cells from SLE patients exhibited diminished CD63 mRNA and enhanced BCL6 mRNA expression(both Po0.05).To sum up,CXCR4 was overexpressed on SLE B cells,positively correlating with disease activity and kidney involvement.Overactivation of the PI3K/Akt and JAK/STAT pathways as well as defective CD63 synthesis may contribute to CXCR4 dysregulation in SLE.
基金
by grants from the National Natural Science Foundation of China(81325019,81630044,81273312,81601432,81550023)
the National Science Fund for Distinguished Young Scholars of China(813250046)
Beijing Municipal Natural Science Foundation(7141008)
the Research Special Fund for Public Welfare Industry of Health(20120217)
the Capital Health Research and Development of Special Fund(2011-4001-02).
