Involvement of distinct PKC gene products in T cell functions

Pfeifhofer-Obermair, Christa; Thuille, Niκolaus; Baier, Gottfried

doi:10.3389/fimmu.2012.00220

Cited by 34 publications

(35 citation statements)

References 139 publications

(159 reference statements)

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“…On the contrary its role in T cell activation seems to be less prominent. This is consistent with data that highlight a central role of other PKC isoforms, namely PKCθ, PKCε and PKCα, in antigen receptor-mediated T cell activation ex vivo and T cell-mediated immunity in vivo [39]. In T cells, however, a role of PKCβ in T cell locomotion has been demonstrated, where T cells crowling has been shown to be associated with the translocation of PKCβ to the microtubule cytoskeleton [41].…”

Section: Discussionsupporting

confidence: 90%

“…[18–20, 34]; PKC family is the largest serine/threonine-specific kinase family known to comprise approximately 2% of the human kinome [35]. It is also clear that different PKCs are not functionally redundant, for example specific PKCs mediate specific cellular signals required for activation, proliferation, differentiation and survival of immune cells [36–39], and patterns of expression for each PKC isoform differ among tissues [18]. Of the classical PKCs isoforms, only PKC-βII was consistently activated during DC-differentiation-inducing stimuli in normal and leukemic progenitors [40].…”

Section: Discussionmentioning

confidence: 99%

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Immunostimulatory effects of RACK1 pseudosubstrate in human leukocytes obtained from young and old donors

et al. 2015

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Aims of this study were to investigate the ability of RACK1 pseudosubstrate alone or in combination with classical immune stimuli to activate human leukocytes, and to restore age-associated immune defects.A total of 25 donors (17 old donors, 77–79 yrs; 8 young donors, 25–34 yrs) were enrolled. To evaluate the effect of RACK1 pseudosubstrate on cytokine production and CD86 expression the whole blood assay was used. Cultures were treated with RACK1 pseudosubstrate in the presence or absence of lipopolysaccharide (LPS) or phytohaemagglutinin (PHA) and incubated for 24 h or 48 h for LPS-induced CD86 expression, TNF-α, IL-6, IL-8, IL-10 production, and PHA-induced IL-4, IL-10, IFN-γ, respectively. RACK1 pseudosubstrate alone induced IL-6, IL-8, and CD86 expression in both young and old donors, and IFN-γ in old donors. In combination with LPS an increase in IL-8, IL-10 and TNF-α was observed, also resulting in restoration of age-associated defective production, while no changes in the other parameters investigated were found.Even if based on a small sample size, these results suggest the possibility to by-pass some of age-associated immune alterations, which may be beneficial in situations were natural immune stimulation is required, and highlight a different role of PKCβ in immune cells activation.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Immunostimulatory effects of RACK1 pseudosubstrate in human leukocytes obtained from young and old donors

et al. 2015

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“…Finally, the aPKCs have only one C1 domain that does not bind DAG, and the cofactors or mechanisms that activate aPKCs are less well understood. In addition, the regulatory region of all PKCs contains a short conserved pseudosubstrate sequence corresponding to an ideal PKC substrate recognition site, with the exception that a Ser/Thr residue, which would normally be phosphorylated, is replaced by an Ala residue (Baier, 2003; Pfeifhofer-Obermair, Thuille, & Baier, 2012). …”

Section: History Structure and Expression Of Pkcθmentioning

confidence: 99%

“…T cells express at various levels up to eight distinct members of the PKC family, i.e ., PKCα, β, δ, ε, η, θ, ζ and ι (Baier, 2003; Hug & Sarre, 1993; Pfeifhofer-Obermair, et al, 2012). The expression of multiple PKC isoforms in T cells suggests functional redundancy and possible specialization.…”

Section: Specialized Functions Of Pkcθ In Conventional T Cells: mentioning

confidence: 99%

The Yin and Yang of Protein Kinase C-theta (PKCθ)

Zhang

Kong

Altman

2013

Advances in Pharmacology

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Protein kinase C-θ (PKCθ) is a PKC family member expressed predominantly in T lymphocytes, and extensive studies addressing its function have been conducted. PKCθ is the only T cell-expressed PKC that localizes selectively to the center of the immunological synapse (IS) following conventional T cell antigen stimulation, and this unique localization is essential for PKCθ-mediated downstream signaling. While playing a minor role in T cell development, early in vitro studies relying, among others, on the use of PKCθ-deficient (Prkcq−/−) T cells revealed that PKCθ is required for the activation and proliferation of mature T cells, reflecting its importance in activating the transcription factors NF-κB, AP-1 and NFAT, as well as for the survival of activated T cells. Upon subsequent analysis of in vivo immune responses in Prkcq−/− mice, it became clear that PKCθ has a selective role in the immune system: It is required for experimental Th2 and Th17-mediated allergic and autoimmune diseases, respectively, and for alloimmune responses, but is dispensable for protective responses against pathogens and for graft-vs.-leukemia responses. Surprisingly, PKCθ was recently found to be excluded from the IS of regulatory T cells (Tregs) and to negatively regulate their suppressive function. These attributes of PKCθ make it an attractive target for catalytic or allosteric inhibitors that are expected to selectively suppress harmful inflammatory and alloimmune responses without interfering with beneficial immunity to infections. Early progress in developing such drugs is being made, but additional studies on the role of PKCθ in the human immune system are urgently needed.

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“…AEB071 blocks the catalytic activity of PKCα, PKCβ and PKCθ isoforms at a low picomolar concentration range, as well as PKCδ, PKCε and PKCηat higher, nanomolar, concentrations [25]. The broad selectivity of AEB071 toward PKC family members could underlie its relative efficacy because other PKCs, in addition to PKCθ, could have compensatory and redundant activities in T cell functions [6,27]. The use of AEB071 has been expanded to other disease settings.…”

Section: Pkc Inhibitorsmentioning

confidence: 99%

Protein kinase C inhibitors for immune disorders

Altman

Kong

2014

Drug Discovery Today

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Protein kinase C (PKC) proteins are a group of well-conserved, intracellular signaling enzymes expressed in all cells and tissues, including immune cells. Much of the molecular insight into PKC immunobiology has been gleaned from studies using PKC gene (Prkc) knockout mice and the analysis of different disease models in these animals. More-recent studies have revealed that PKCs also have crucial roles in the pathogenesis of human immune disorders. Therefore, strategies to modulate the functions of PKC enzymes could have a major impact on the treatment and therapies of autoimmune diseases and other immune disorders.

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Involvement of distinct PKC gene products in T cell functions

Cited by 34 publications

References 139 publications

Immunostimulatory effects of RACK1 pseudosubstrate in human leukocytes obtained from young and old donors

Immunostimulatory effects of RACK1 pseudosubstrate in human leukocytes obtained from young and old donors

The Yin and Yang of Protein Kinase C-theta (PKCθ)

Protein kinase C inhibitors for immune disorders

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