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

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. 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.

Suppression of cell migration by protein kinase Cδ

“…We next examined the mobility of MEFs from wild type and PKCd knockout mice (Miyamoto et al, 2002). The lack of PKCd in the MEFs from the PKCd knockout mice was verified by Western blot (Figure 4a).…”

“…Such mice were resistant to the tumor promoting effects of phorbol esters (Reddig et al, 1999). Other studies have also suggested negative effects for PKCd on cell proliferation (Mischak et al, 1993;Acs et al, 1997), and studies of PKCd knockout mice recently demonstrated negative regulation of B-cell proliferation by PKCd (Miyamoto et al, 2002). PKCd was recently reported to respond to DNA damage by activating the stress-activated protein kinase (SAPK/ JNK) signaling pathway (Yoshida et al, 2002), which negatively regulates cell proliferation.…”

Protein kinase C-delta (PKCδ), a marker of inflammation and tuberculosis disease progression in humans, is important for optimal macrophage killing effector functions and survival in mice

“…6,7 PKCd À / À mice were originally characterized by two independent research groups who highlighted the role of this kinase in B-cell anergy 8 and B cell-mediated autoimmunity. 9 Furthermore, PKCd À / À mice were protected against glucose intolerance induced by high-fat diet by exhibiting reduced accumulation of liver triacylglycerol and impaired production of lipogenic enzymes. 10 This feature of accumulating fewer lipids during an inflammatory condition by PKCd À / À mice upon Mycobacterium tuberculosis (Mtb) infection might impair its ability to undergo slow-replicating, persistence phase as reported in human sputum.…”

New PKCδ family members, PKCδIV, δV, δVI, and δVII are specifically expressed in mouse testis

“…Leitges et al described that PKCd À/À mice developed normally and were fertile [44]. Miyamoto et al did not report if PKCd null mice were normally fertile or not [45]. In null mice, Leitges et al altered the exon containing the first methionine, (exon2 in this paper), and replaced it with a LacZ gene.…”