Aberrant CD40-induced NF-κB activation in human lupus B lymphocytes

PLoS One. 2012;7(8):e41644. doi: 10.1371/journal.pone.0041644. Epub 2012 Aug 27.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Active Transport, Cell Nucleus
  • Adolescent
  • Adult
  • B-Lymphocytes / cytology*
  • B-Lymphocytes / metabolism
  • CD40 Antigens / metabolism*
  • CD40 Ligand / biosynthesis
  • Child
  • Female
  • Gene Expression Regulation*
  • Humans
  • I-kappa B Proteins / metabolism
  • Lupus Erythematosus, Systemic / blood*
  • Lupus Erythematosus, Systemic / metabolism
  • Membrane Microdomains / metabolism
  • Middle Aged
  • NF-KappaB Inhibitor alpha
  • NF-kappa B / metabolism*
  • Palatine Tonsil / immunology
  • Palatine Tonsil / metabolism
  • Phosphorylation
  • Signal Transduction

Substances

  • CD40 Antigens
  • I-kappa B Proteins
  • NF-kappa B
  • NFKBIA protein, human
  • NF-KappaB Inhibitor alpha
  • CD40 Ligand

Grants and funding

This work was supported by National Natural Science Foundation of China (81172858, 30972731), National High Technology Research and Development Project of China (973 Project) (2007CB512405). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.