NF-kappaB is required for CD38-mediated induction of C(gamma)1 germline transcripts in murine B lymphocytes.
Ligation of CD38 on murine B cells with agonistic anti-CD38 mAb induces B cell proliferation, expression of germline gamma1 transcripts and enhances IL-5 receptor expression. This leads to Ig class switch recombination from the micro to gamma1 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 gamma1 transcript expression in B cells are poorly understood. Here we show that CD38 ligation of murine splenic B cells activates members of the NF-kappaB/Rel family of proteins including c-Rel, p65 and p50. The activation patterns and kinetics of NF-kappaB-like proteins in CD38-stimulated B cells differ somewhat from those seen in CD40-stimulated B cells. Activation of NF-kappaB-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-kappaB 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-kappaB in CD38-stimulated murine B cells. Consistent with a role for NF-kappaB/Rel signaling in CD38-mediated germline gamma1 transcript expression, p50(-/-) B cells show significant impairment of germline gamma1 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 gamma1 transcript expression in response to CD38 or CD40 ligation. These results indicate an essential role for NF-kappaB proteins in the induction of germline gamma1 transcripts by CD38-ligated murine B cells giving rise to IL-5-induced IgG1 production.
Division of Immunology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Japan.
Hiroaki
H
Kaku
Keisuke
K
Horikawa
Yuichi
Y
Obata
Ichiro
I
Kato
Hiroshi
H
Okamoto
Nobuo
N
Sakaguchi
Steve
S
Gerondakis
Kiyoshi
K
Takatsu
D036541:ADP-ribosyl Cyclase / Q000276:immunology*; D051997:ADP-ribosyl Cyclase 1; D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D000906:Antibodies / Q000276:immunology; D015703:Antigens, CD / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology / Q000502:physiology*; D005260:Female; D007074:Immunoglobulin G / Q000096:biosynthesis / Q000235:genetics; D007075:Immunoglobulin M / Q000096:biosynthesis / Q000235:genetics; D007142:Immunoglobulin gamma-Chains / Q000235:genetics; D015848:Interleukin-5 / Q000502:physiology; D008562:Membrane Glycoproteins; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000502:physiology*; D011505:Protein-Tyrosine Kinases / Q000502:physiology; D013154:Spleen / Q000276:immunology / Q000502:physiology
D000906:Antibodies; D015703:Antigens, CD; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D007142:Immunoglobulin gamma-Chains; D015848:Interleukin-5; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625951:Btk protein, mouse; D036541:ADP-ribosyl Cyclase; C498155:Cd38 protein, mouse; D051997:ADP-ribosyl Cyclase 1