International Immunology, Vol. 14, No. 9, pp. 1055-1064,
September 2002
© 2002 Japanese Society for Immunology
NF-
B is required for CD38-mediated induction of C
1 germline transcripts in murine B lymphocytes
1 Division of Immunology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan 2 Department of Pathology, Aichi Cancer Center, Nagoya 464-8681, Japan 3 Department of Biochemistry, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan 4 Department of Immunology, Kumamoto University School of Medicine, Kumamoto 960-8575, Japan 5 Walter and Eliza Hall Institute of Medical Research, Royal Melbourne Hospital, Victoria 3050, Australia
The first two authors contributed equally to this work
Correspondence to: K. Takatsu; E-mail: takatsuk{at}ims.u-tokyo.ac.jp
Transmitting editor: K. Sugamura
Ligation of CD38 on murine B cells with agonistic anti-CD38 mAb induces B cell proliferation, expression of germline 
1 transcripts and enhances IL-5 receptor expression. This leads to Ig class switch recombination from the µ to 1 heavy chain gene, and high levels of IgM and lgG1 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 1 transcript expression in B cells are poorly understood. Here we show that CD38 ligation of murine splenic B cells activates members of the NF-
B/Rel family of proteins including c-Rel, p65 and p50. The activation patterns and kinetics of NF-B-like proteins in CD38-stimulated B cells differ somewhat from those seen in CD40-stimulated B cells. Activation of NF-B-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 (PI)-3 kinase also suppressing NF-B activation in CD38-activated B cells. We infer from these results that activation of Btk, PI-3 kinase and PKC play, at least in part, important roles in the induction of NF-B in CD38-stimulated murine B cells. Consistent with a role for NF-B/Rel signaling in CD38-mediated germline 1 transcript expression, p50–/– B cells show significant impairment of germline 1 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 1 transcript expression in response to CD38 or CD40 ligation. These results indicate an essential role for NF-B proteins in the induction of germline 1 transcripts by CD38-ligated murine B cells giving rise to IL-5-induced IgG1 production.
Keywords: Bruton’s tyrosine kinase, c-Rel, IgH switch recombination, IL-5, phosphatidylinositol-3 kinase, transcription factors
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