Protein Kinase C βII Plays an Essential Role in Dendritic Cell Differentiation and Autoregulates Its Own Expression

Abstract

Dendritic cells (DC) arise from a diverse group of hematopoietic progenitors and have marked phenotypic and functional heterogeneity. The signal transduction pathways that regulate the ability of progenitors to undergo DC differentiation, as well as the specific characteristics of the resulting DC, are only beginning to be characterized. We have found previously that activation of protein kinase C (PKC) by cytokines or phorbol esters drives normal human CD34؉ hematopoietic progenitors and myeloid leukemic blasts (KG1, K562 cell lines, and primary patient blasts) to differentiate into DC. We now report that PKC activation is also required for cytokinedriven DC differentiation from monocytes. Of the cPKC isoforms, only PKC-␤II was consistently activated by DC differentiation-inducing stimuli in normal and leukemic progenitors. Transfection of PKC-␤II into the differentiation-resistant KG1a subline restored the ability to undergo DC differentiation in a signal strength-dependent fashion as follows: 1) by development of characteristic morphology; 2) the up-regulation of DC surface markers; 3) the induction of expression of the NFB family member Rel B; and 4) the potent ability to stimulate allo-T cells. Most unexpectedly, the restoration of PKC-␤II signaling in KG1a was not directly due to overexpression of the transfected classical PKC (␣, ␤II, or ␥) but rather through induction of endogenous PKC-␤ gene expression by the transfected classical PKC. The mechanism of this positive autoregulation involves up-regulation of PKC-␤ promoter activity by constitutive PKC signaling. These findings indicate that the regulation of PKC-␤II expression and signaling play critical roles in mediating progenitor to DC differentiation.

Protein Kinase C Inhibitor Generates Stable Human Tolerogenic Dendritic Cells

“…It has been reported that modulation of cellular individual PKC activity induces PKC-dependent cell differentiation and cytokine production in many cell types (40). PKC has been reported to play critical roles in mediating progenitor-to-DC differentiation and cytokine production from monocytes/macrophages and DCs (41)(42)(43)(44)(45)(46). In the present study, we found that stable tDCs showing high production of IL-10 were generated by addition of PKCI during the process of maturation from iDCs.…”

Involvement of the PRKCB1 gene in autistic disorder: significant genetic association and reduced neocortical gene expression

“…23,24,26,[28][29][30][31] These results revealed that coordinated expression patterns are lost for several cytokines and enzymes involved in oxidative stress, maintained to a large extent for others, and entirely preserved for extracellular matrix proteins (Table 6). In addition to the loss of correlation with PKCb transcript levels, many of these genes also displayed significant expression differences between autistic and control brains, including TGFb2, MCP1, collagen IV and fibronectin 1 ( Table 6).…”

“…[15][16][17][18][19] In the immune system, PKCb isoenzymes play a critical role in B-cell receptor-mediated responses, T-cell migration and cytokine secretion, dendritic cell differentiation and monocyte and macrophage functioning. [20][21][22][23][24][25] In the gut, PKCbI and bII are expressed by epithelial cells, where they regulate intestinal permeability and cell proliferation, respectively. [26][27][28] In the kidney, both PKCb isoforms are expressed by mesangial cells and play a major role in diabetic nephropathy and albuminuria, possibly through oxidative stress.…”

“…These expression changes can currently be best interpreted as a compensatory adjustment aimed at hampering a dysregulated immune response affecting the CNS of autistic patients. The negative-feedback loop mediating this compensatory adjustment is Table 6 Pearson correlation coefficients for PRKCB1 and genes whose expression is either directly or indirectly modulated by PKCb, 23,24,26,[28][29][30][31] assessed in autistic patients (rAUT) and in matched controls (rCON); differences in mRNA levels between cases and controls, expressed as difference in average log2 ratios [ALR (aut-con)], and relative paired and rank P-values; coordinated expression patterns are (A) lost for several cytokines and enzymes involved in oxidative stress, (B) maintained to some extent for others and (C) largely preserved for extracellular matrix molecules …”

Sensitization of IL-2 Signaling through TLR-7 Enhances B Lymphoma Cell Immunogenicity

“…The immunogenic importance of PKC (likely the PKC␤ isozyme) has been documented previously (3,4,16,34), although the mechanism is not entirely clear. PKC agonists increased CD83 expression (Fig.…”