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Increased proliferation of B cells and auto-immunity in mice lacking protein kinase Cδ

Nature volume 416, pages 865–869 (2002)Cite this article

Abstract

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 development1,2,3,4. Among the PKC isotypes, PKC-δ is unique in that its overexpression results in inhibition of cell growth5,6,7,8,9,10,11. Here we show that mice that lack PKC-δ 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-δ-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-δ-null mice as a result of an increase in the DNA-binding activity of NF-IL6. Furthermore, the PKC-δ-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-δ has an indispensable function in negative regulation of B-cell proliferation, and is particularly important for the establishment of B-cell tolerance.

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Figure 1: Targeted disruption of the mouse PKC-δ gene.
Figure 2: Expansion of the B-lymphocyte population in PKC-δ-/- mice.
Figure 3: Increased proliferative capacity of B cells from PKC-δ-/- mice.
Figure 4: Increased serum concentrations of IgG1, IgA and auto-antibodies in PKC-δ-/- mice.
Figure 5: Glomerulonephritis and perivascular infiltration of leukocytes in PKC-δ-/- mice.

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References

  1. Nishizuka, Y. Protein kinase C and lipid signaling for sustained cellular responses. FASEB J. 9, 484–496 (1995)

    Article  CAS  Google Scholar 

  2. Mellor, H. & Parker, P. J. The extended protein kinase C superfamily. Biochem. J. 332, 281–292 (1998)

    Article  CAS  Google Scholar 

  3. Livneh, E. & Fishman, D. D. Linking protein kinase C to cell-cycle control. Eur. J. Biochem. 248, 1–9 (1997)

    Article  CAS  Google Scholar 

  4. Weiss, A. & Littman, D. R. Signal transduction by lymphocyte antigen receptors. Cell 76, 263–274 (1994)

    Article  CAS  Google Scholar 

  5. Ohno, S., Akita, Y., Konno, Y., Imajoh, S. & Suzuki, K. A novel phorbol ester receptor/protein kinase, nPKC, distantly related to the protein kinase C family. Cell 53, 731–741 (1988)

    Article  CAS  Google Scholar 

  6. Gschwendt, M. Protein kinase Cδ. Eur. J. Biochem. 259, 555–564 (1999)

    Article  CAS  Google Scholar 

  7. Watanabe, T. et al. Cell division arrest induced by phorbol ester in CHO cells overexpressing protein kinase C-δ subspecies. Proc. Natl Acad. Sci. USA 89, 10159–10163 (1992)

    Article  ADS  CAS  Google Scholar 

  8. Mischak, H. et al. Overexpression of protein kinase C-δ and -ε in NIH 3T3 cells induces opposite effects on growth, morphology, anchorage dependence, and tumorigenicity. J. Biol. Chem. 268, 6090–6096 (1993)

    CAS  PubMed  Google Scholar 

  9. Fukumoto, S. et al. Protein kinase Cδ inhibits the proliferation of vascular smooth muscle cells by suppressing G1 cyclin expression. J. Biol. Chem. 272, 13816–13822 (1997)

    Article  CAS  Google Scholar 

  10. Mishima, K., Ohno, S., Shitara, N., Yamaoka, K. & Suzuki, K. Opposite effects of the overexpression of protein kinase Cγ and δ on the growth properties of human glioma cell line U251 MG. Biochem. Biophys. Res. Commun. 201, 363–372 (1994)

    Article  CAS  Google Scholar 

  11. Harrington, E. O. et al. Enhancement of migration by protein kinase Cα and inhibition of proliferation and cell cycle progression by protein kinase Cδ in capillary endothelial cells. J. Biol. Chem. 272, 7390–7397 (1997)

    Article  CAS  Google Scholar 

  12. Pessino, A. et al. Antisense oligodeoxynucleotide inhibition of δ protein kinase C expression accelerates induced differentiation of murine erythroleukaemia cells. Biochem. J. 312, 549–554 (1995)

    Article  CAS  Google Scholar 

  13. Li, W. & Pierce, J. H. Protein kinase C-δ, an important signaling molecule in the platelet-derived growth factor β receptor pathway. Curr. Topics Microbiol. Immunol. 211, 55–65 (1996)

    CAS  Google Scholar 

  14. Mischak, H. et al. Phorbol ester-induced myeloid differentiation is mediated by protein kinase C-α and -δ and not by protein kinase C-β II, -ε, -ζ, and -η. J. Biol. Chem. 268, 20110–20115 (1993)

    CAS  PubMed  Google Scholar 

  15. Emoto, Y., Kisaki, H., Manome, Y., Kharbanda, S. & Kufe, D. Activation of protein kinase Cδ in human myeloid leukemia cells treated with 1-β-d-arabinofuranosylcytosine. Blood 87, 1990–1996 (1996)

    CAS  PubMed  Google Scholar 

  16. Emoto, Y. et al. Proteolytic activation of protein kinase Cδ by an ICE-like protease in apoptotic cells. EMBO J. 14, 6148–6156 (1995)

    Article  CAS  Google Scholar 

  17. Ghayur, T. et al. Proteolytic activation of protein kinase Cδ by an ICE/CED 3-like protease induces characteristics of apoptosis. J. Exp. Med. 184, 2399–2404 (1996)

    Article  CAS  Google Scholar 

  18. Li, W. et al. Expression of an ATP binding mutant of PKC-δ inhibits Sis-induced transformation of NIH3T3 cells. Oncogene 13, 731–737 (1996)

    CAS  Google Scholar 

  19. La Porta, C. A. & Comolli, R. Over-expression of protein kinase Cδ is associated with a delay in preneoplastic lesion development in diethylnitrosamine-induced rat hepatocarcinogenesis. Carcinogenesis 16, 1233–1238 (1995)

    Article  CAS  Google Scholar 

  20. Geiges, D., Marks, F. & Gschwendt, M. Loss of protein kinase Cδ from human HaCaT keratinocytes upon ras transfection is mediated by TGF α. Exp. Cell Res. 219, 299–303 (1995)

    Article  CAS  Google Scholar 

  21. Lu, Z. et al. Tumor promotion by depleting cells of protein kinase Cδ. Mol. Cell. Biol. 17, 3418–3428 (1997)

    Article  CAS  Google Scholar 

  22. Reddig, P. J. et al. Transgenic mice overexpressing protein kinase Cδ in the epidermis are resistant to skin tumor promotion by 12-O-tetradecanoylphorbol-13-acetate. Cancer Res. 59, 5710–5718 (1999)

    CAS  PubMed  Google Scholar 

  23. Akira, S. & Kishimoto, T. IL-6 and NF-IF6 in acute-phase response and viral infection. Immunol. Rev. 127, 25–50 (1992)

    Article  CAS  Google Scholar 

  24. Trautwein, C., van der Geer, P., Karin, M., Hunter, T. & Chojkier, M. Protein kinase A and C site-specific phosphorylations of LAP (NF-IL6) modulate its binding affinity to DNA recognition elements. J. Clin. Invest. 93, 2554–2561 (1994)

    Article  CAS  Google Scholar 

  25. Leitges, M. et al. Immunodeficiency in protein kinase Cβ-deficient mice. Science 273, 788–791 (1996)

    Article  ADS  CAS  Google Scholar 

  26. Sun, Z. et al. PKC-θ is required for TCR-induced NF-κB activation in mature but not immature T lymphocytes. Nature 404, 402–407 (2000)

    Article  ADS  CAS  Google Scholar 

  27. Suematsu, S. et al. IgG1 plasmacytosis in interleukin 6 transgenic mice. Proc. Natl Acad. Sci. USA 86, 7547–7551 (1989)

    Article  ADS  CAS  Google Scholar 

  28. Nakayama, K. et al. Mice lacking p27Kip1 display increased body size, multiple organ hyperplasia, retinal dysplasia, and pituitary tumors. Cell 85, 707–720 (1996)

    Article  CAS  Google Scholar 

  29. Tsukiyama, T. et al. Down-regulation of p27Kip1 expression is required for development and function of T cells. J. Immunol. 166, 304–312 (2001)

    Article  CAS  Google Scholar 

  30. Burlingame, R. W. & Rubin, R. L. Subnucleosome structures as substrates in enzyme-linked immunosorbent assays. J. Immunol. Methods 134, 187–199 (1990)

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank S. Akira and K. Hoshino for the plasmids; N. Motoyama, A. Yoshimura and U. Kikkawa for discussions; Y. Yamada, K. Shimoharada and N. Ohtsuji for technical assistance; and M. Kimura and C. Sugita for help in preparation of the manuscript. This work was supported in part by a grant from the Ministry of Education, Science, Sports and Culture of Japan, by Nissan Science Foundation, and by a research grant from the Human Frontier Science Program.

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Authors and Affiliations

  1. Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, 812-8582, Japan

    Akitomo Miyamoto, Hiroyuki Imaki, Tadasuke Tsukiyama, Hiroyasu Nagahama, Shigetsugu Hatakeyama & Keiichi I. Nakayama

  2. CREST, Japan Science and Technology Corporation, Kawaguchi, 332-0012, Saitama, Japan

    Akitomo Miyamoto, Keiko Nakayama, Hiroyuki Imaki, Sachiko Hirose, Tadasuke Tsukiyama, Hiroyasu Nagahama, Shigetsugu Hatakeyama & Keiichi I. Nakayama

  3. Department of Molecular Genetics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, 812-8582, Japan

    Keiko Nakayama & Keiichi I. Nakayama

  4. Second Department of Pathology, Juntendo University School of Medicine, Bunkyo-ku, 113-8421, Tokyo, Japan

    Sachiko Hirose, Yi Jiang & Masaaki Abe

  5. Department of Molecular Biology, Yokohama City University School of Medicine, Yokohama, 236-0004, Kanagawa, Japan

    Shigeo Ohno

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Miyamoto, A., Nakayama, K., Imaki, H. et al. Increased proliferation of B cells and auto-immunity in mice lacking protein kinase Cδ. Nature 416, 865–869 (2002). https://doi.org/10.1038/416865a

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