Increased proliferation of B cells and auto-immunity in mice lacking protein kinase Cdelta.
Protein kinase C (PKC), which comprises 11 closely related isoforms, has been implicated in a wide variety of cellular processes, such as growth, differentiation, secretion, apoptosis and tumour development. Among the PKC isotypes, PKC-delta is unique in that its overexpression results in inhibition of cell growth. Here we show that mice that lack PKC-delta exhibit expansion of the B-lymphocyte population with the formation of numerous germinal centres in the absence of stimulation. The rate of proliferation in response to stimulation was greater for B cells from PKC-delta-deficient mice than for those from wild-type mice. Adoptive transfer experiments suggested that the hyperproliferation phenotype is B-cell autonomous. Production of interleukin-6 was markedly increased in B cells of PKC-delta-null mice as a result of an increase in the DNA-binding activity of NF-IL6. Furthermore, the PKC-delta-deficient mice contain circulating autoreactive antibodies and display immune-complex-type glomerulonephritis, as well as lymphocyte infiltration in many organs. These results suggest that PKC-delta has an indispensable function in negative regulation of B-cell proliferation, and is particularly important for the establishment of B-cell tolerance.
Miyamoto
Akimoto
A
Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan.
Nakayama
Keiko
K
Imaki
Hiroyuki
H
Hirose
Sachiko
S
Jiang
Yi
Y
Abe
Masaaki
M
Tsukiyama
Tadasuke
T
Nagahama
Hiroyasu
H
Ohno
Shigeo
S
Hatakeyama
Shigetsugu
S
Nakayama
Keiichi I
KI
D019264:Adoptive Transfer; D000818:Animals; D001323:Autoantibodies / Q000097:blood; D015551:Autoimmunity / Q000276:immunology*; D001402:B-Lymphocytes / Q000166:cytology* / Q000276:immunology* / Q000637:transplantation; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000378:metabolism; D002455:Cell Division; D005434:Flow Cytometry; D017353:Gene Deletion; D016654:Genes, RAG-1 / Q000235:genetics; D005921:Glomerulonephritis / Q000276:immunology / Q000473:pathology; D007108:Immune Tolerance / Q000276:immunology; D007070:Immunoglobulin A / Q000097:blood; D007074:Immunoglobulin G / Q000097:blood; D016753:Interleukin-10 / Q000235:genetics; D015850:Interleukin-6 / Q000096:biosynthesis / Q000235:genetics; D007527:Isoenzymes / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D007668:Kidney / Q000276:immunology / Q000473:pathology; D008198:Lymph Nodes / Q000166:cytology / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D011493:Protein Kinase C / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D051745:Protein Kinase C-delta; D013154:Spleen / Q000166:cytology / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology
D001323:Autoantibodies; D022782:CCAAT-Enhancer-Binding Protein-beta; D007070:Immunoglobulin A; D007074:Immunoglobulin G; D015850:Interleukin-6; D007527:Isoenzymes; D016753:Interleukin-10; C497259:Prkcd protein, mouse; D011493:Protein Kinase C; D051745:Protein Kinase C-delta