NF-κB is required for CD38-mediated induction of Cγ1 germline transcripts in murine B lymphocytes

Hiroaki Kaku, Keisuke Horikawa, Yuichi Obata, Ichiro Kato, Hiroshi Okamoto, Nobuo Sakaguchi, Steve Gerondakis, Kiyoshi Takatsu

Research output: Contribution to journalArticleResearchpeer-review

35 Citations (Scopus)

Abstract

Ligation of CD38 on murine B cells with agonistic anti-CD38 mAb induces B cell proliferation, expression of germline γ1 transcripts and enhances IL-5 receptor expression. This leads to Ig class switch recombination from the μ to γ1 heavy chain gene, and high levels of IgM and IgG1 production, particularly in response to anti-CD38 and IL-5 co-stimulation. Although some of the post-receptor signaling events initiated by CD38 ligation have been characterized, signaling pathways involved in CD38-mediated germline γ1 transcript expression in B cells are poorly underslood. Here we show that CD38 ligation of murine splenic B cells activates members of the NF-κB/Rel family of proteins including c-Rel, p65 and p50. The activation patterns and kinetics of NF-κB-like proteins in CD38-stlmulated B cells differ somewhat from those seen in CD40-stimulated B cells. Activation of NF-κB-like proteins by CD38 ligation is not observed in splenic B cells from Bruton's tyrosine kinase (Btk)-deficient (Btk-/-) mice, with inhibitors of protein kinase C (PKC) and phosphatidylinositol (Pl)-3 kinase also suppressing NF-κB activation in CD38-activated B cells. We infer from these results that activation of Btk, Pl-3 kinase and PKC play, at least in part, important roles in the induction of NF-κB in CD38-stimulated murine B cells. Consistent with a role for NF-κB/Rel signaling in CD38-mediated germline γ1 transcript expression, p50-/- B cells show significant impairment of germline γ1 transcript expression in response to CD38 ligation, whereas the CD40-induced response was not altered. In contrast, c-Rel-/- B cells show a severe impairment of germline γ1 transcript expression in response to CD38 or CD40 ligation. These results indicate an essential role for NF-κB proteins in the induction of germline γ1 transcripts by CD38-ligated murine B cells giving rise to IL-5-Induced IgG1 production.

Original languageEnglish
Pages (from-to)1055-1064
Number of pages10
JournalInternational Immunology
Volume14
Issue number9
Publication statusPublished - 1 Sep 2002
Externally publishedYes

Keywords

  • Bruton's tyrosine kinase
  • c-Rel
  • IgH switch recombination
  • IL-5
  • Phosphatidylinositol-3 kinase
  • Transcription factors

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