title: Aberrant CD40-induced NF-κB activation in human lupus B lymphocytes.
abstract: Auto-reactive B lymphocytes and its abnormal CD40 signaling play important roles in the pathogenesis of systemic lupus erythematosus (SLE). In this study, we analyzed CD40 expression and CD40/CD154 induced activation of NF-κB signaling pathway in B cells from SLE patients. B cells from healthy volunteers and tonsilar B cells from chronic tonsillitis were used as negative and positive controls. Results showed CD40-induced NF-κB signaling was constitutively activated in B cells from active lupus patients, including decreased CD40 in raft portion, increased phosphorylation and degradation of IκBα, phosphorylation of P65, as well as increased nuclear translocation of P65, P50, c-Rel, which could be blocked by anti-CD154. CD154 stimulation could induce further phosphorylation and degradation of IκBα, as well as phosphorylation of P65 and nuclear translocation of P65. In addition, CD40-induced kinase activities in B cells from lupus patients mimicked that of tonsil B cells, in that IKKα/β were more activated compared to normal B cells. CD40-induced NF-κB activity was blocked by both IκB phosphorylation and proteosome degradation inhibitors in both lupus and normal B cells. All together, our findings revealed that canonical NF-κB signaling is constitutively activated in active lupus and is mediated by CD154/CD40. CD40 induced NF-κB activation is different in human lupus B lymphocytes compared with normal B cells.
authors.affiliation: Department of Rheumatology, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Science, Beijing, China.
authors.forename: Wen
authors.initials: W
authors.lastname: Zhang
authors.forename: Qun
authors.initials: Q
authors.lastname: Shi
authors.forename: Xiaotian
authors.initials: X
authors.lastname: Xu
authors.forename: Hua
authors.initials: H
authors.lastname: Chen
authors.forename: Wei
authors.initials: W
authors.lastname: Lin
authors.forename: Fengchun
authors.initials: F
authors.lastname: Zhang
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Zeng
authors.forename: Xuan
authors.initials: X
authors.lastname: Zhang
authors.forename: Denian
authors.initials: D
authors.lastname: Ba
authors.forename: Wei
authors.initials: W
authors.lastname: He
mesh_terms: D021581:Active Transport, Cell Nucleus; D000293:Adolescent; D000328:Adult; D001402:B-Lymphocytes / Q000166:cytology* / Q000378:metabolism; D019013:CD40 Antigens / Q000378:metabolism*; D023201:CD40 Ligand / Q000096:biosynthesis; D002648:Child; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D008180:Lupus Erythematosus, Systemic / Q000097:blood* / Q000378:metabolism; D021962:Membrane Microdomains / Q000378:metabolism; D008875:Middle Aged; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D014066:Palatine Tonsil / Q000276:immunology / Q000378:metabolism; D010766:Phosphorylation; D015398:Signal Transduction
chemical_list: D019013:CD40 Antigens; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D000072000:NF-KappaB Inhibitor alpha; D023201:CD40 Ligand