1. Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan
2. CREST, Japan Science and Technology Corporation, Kawaguchi, Saitama 332-0012, Japan
3. Department of Molecular Genetics, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan
4. Second Department of Pathology, Juntendo University School of Medicine, Bunkyo-ku, Tokyo 113-8421, Japan
5. Department of Molecular Biology, Yokohama City University School of Medicine, Yokohama, Kanagawa 236-0004, Japan

Correspondence to: Keiichi I. Nakayama^1,2,3 Correspondence and requests for materials should be addressed to K.I.N. (e-mail: Email: nakayak1@bioreg.kyushu-u.ac.jp).

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 development^{1, 2, 3, 4}. Among the PKC isotypes, PKC- is unique in that its overexpression results in inhibition of cell growth^{5, 6, 7, 8, 9, 10, 11}. Here we show that mice that lack PKC- 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--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--null mice as a result of an increase in the DNA-binding activity of NF-IL6. Furthermore, the PKC--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- has an indispensable function in negative regulation of B-cell proliferation, and is particularly important for the establishment of B-cell tolerance.