Involvement of PKCα/β in TLR4 and TLR2 dependent activation of NF-κB

Asehnoune, Karim; Strassheim, Derek; Mitra, Sanchayita; Kim, Jae Yeol; Abraham, Edward

doi:10.1016/j.cellsig.2004.08.005

Cited by 110 publications

(80 citation statements)

References 41 publications

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“…We demonstrated that cPKC, particularly PKC-a isoform, participates in MyD88-dependent TLR/IL-1R-induced inflammatory/immunomodulatory cytokine expression by regulating the activation of NF-kB and MAPK pathways. The cPKC family was previously shown to couple to TLR2 and TLR4-dependent NF-kB activation in murine neutrophils and rat MF [16,29]. Recently, we reported that cPKC-a is a component of dsRNAmediated TLR3 and dsDNA signaling that controls IRF3-mediated IFN-b transcription while it does not influence NF-kB and MAPK pathways in human cells [15].…”

Section: Discussionmentioning

confidence: 93%

“…Results cPKC inhibitors decrease MyD88-mediated cytokine synthesis in human DC TLR2 stimulation by peptidoglycan was previously shown to induce PKC-ab activation in murine neutrophils [16]. We therefore assessed the phosphorylation status of cPKC in human moDC and revealed that fibrolast-stimulating lipopeptide (FSL)-1, a ligand for TLR2/6 heterodimer, induced activation of cPKC.…”

Section: Introductionmentioning

confidence: 99%

“…We demonstrated that PKC-a participates in the induction of inflammatory/immunomodulatory gene expression mediated by a number of MyD88-dependent TLR ligands downstream of the adapter MyD88 in human and murine DC. Overall, our demonstration of a differential role of PKC-a activity in human and mouse cells downstream of TRIF indicates a divergence in the coupling of PKC-a within TLR signaling network between species.Results cPKC inhibitors decrease MyD88-mediated cytokine synthesis in human DC TLR2 stimulation by peptidoglycan was previously shown to induce PKC-ab activation in murine neutrophils [16]. We therefore assessed the phosphorylation status of cPKC in human moDC and revealed that fibrolast-stimulating lipopeptide (FSL)-1, a ligand for TLR2/6 heterodimer, induced activation of cPKC.…”

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confidence: 99%

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PKC‐α controls MYD88‐dependent TLR/IL‐1R signaling and cytokine production in mouse and human dendritic cells

et al. 2010

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Conventional PKC (cPKC)-a regulates TRIF-dependent IFN response factor 3 (IRF3)-mediated gene transcription, but its role in MyD88-dependent TLR signaling remains unknown. Herein, we demonstrate that PKC-a is induced by several MyD88-dependent TLR/IL-1R ligands and regulates cytokine expression in human and murine DC. First, inhibition of cPKC activity in human DC by cPKC-specific inhibitors, Gö 6976 or HBDDe, downregulated the production of classical inflammatory/immunomodulatory cytokines induced by TLR2, TLR5 or IL-1R but not by TLR3 stimulation. Similarly, dominant negative PKC-a repressed Pam 3 CSK 4 induced NF-jB-and AP-1-driven promoter activities in TLR2-expressing human embryonic kidney 293 T cells. Dominant negative PKC-a inhibited NF-jB reporter activity mediated by overexpression of MyD88 but not TRIF. Unexpectedly, BM-derived DC from PKC-a À/À mice exhibited decreased TNF-a and IL-12p40 production induced by both MyD88-and TRIF-dependent ligands. Furthermore, PKC-a is coupled to TLR2 signaling proximal to MyD88 since MAPK and IjB kinase-a/b phosphorylations and IjBa degradation were inhibited in PKC-a À/À BM-derived DC. Finally, co-immunoprecipitation assays revealed that PKC-a physically interacts with Pam 3 CSK 4 activated TLR2 in WT but not in MyD88 À/À DC. Collectively this study identifies a species-specific role of PKC-a as a key component that controls MyD88-dependent cytokine gene expression in human and mouse but differentially regulates production of TRIF-dependent cytokines.Key words: MyD88 . PKC . TLR Supporting Information available online Introduction TLR are a family of evolutionary conserved transmembrane proteins that are expressed on numerous cell types including Mf and DC. They function as pathogen recognition receptors, sensing a wide range of invading pathogens including bacteria, fungi and viruses through recognition of PAMP. Engagement of TLR by microbial products triggers the activation of two distinct signaling pathways: the MyD88-dependent and -independent pathways, Ã These authors contributed equally to this work.ÃÃ These authors contributed equally to this work. [4,5]. Recent studies identified several PKC isoforms as key regulators of TLR signaling pathways. PKC serine/threonine kinase family is classified into three groups according to their structure homology and co-factor regulation (conventional PKC (a, bI, bII, and g), novel PKC (d, e, y and Z/L) and atypical PKC (l/i and z)) [6,7]. PKC-e À/À Mf display a major defect in their ability to generate inflammatory mediators in response to LPS and are highly susceptible to Gram-positive and Gram-negative infections [8,9]. PKC-e is also involved in LPS-induced MAPK phosphatase 1 expression in MF and plays a critical role in LPS-induced IL-12p70 and TNF-a production in DC [10,11]. PKC-e À/À and PKC-d À/À MF display an impaired activation of NF-kB and MAPK downstream of TLR2 and TLR4 [8,12]. PKC-d is necessary to induce Stat-1 activation in response to LPS in murine MF [13]. PKC-z is implicated in LPS-induced MAPK and NF-kB...

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Section: Discussionmentioning

confidence: 93%

Section: Introductionmentioning

confidence: 99%

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confidence: 99%

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PKC‐α controls MYD88‐dependent TLR/IL‐1R signaling and cytokine production in mouse and human dendritic cells

et al. 2010

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“…82 As will be discussed below, several other parallel pathways have an impact on TLR4-mediated NF-kB activation, including PI3K, receptor-interacting protein (RIP) and the MAPKs. In nonendothelial cells, various PKC isoforms have also been implicated in NF-kB activation 83,84 (Figure 1). …”

Section: Myd88-dependent Signalingmentioning

confidence: 99%

Lipopolysaccharide signaling in endothelial cells

Dauphinee

Karsan

2006

Laboratory Investigation

524

426

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Sepsis is the systemic immune response to severe bacterial infection. The innate immune recognition of bacterial and viral products is mediated by a family of transmembrane receptors known as Toll-like receptors (TLRs). In endothelial cells, exposure to lipopolysaccharide (LPS), a major cell wall constituent of Gramnegative bacteria, results in endothelial activation through a receptor complex consisting of TLR4, CD14 and MD2. Recruitment of the adaptor protein myeloid differentiation factor (MyD88) initiates an MyD88-dependent pathway that culminates in the early activation of nuclear factor-jB (NF-jB) and the mitogen-activated protein kinases. In parallel, a MyD88-independent pathway results in a late-phase activation of NF-jB. The outcome is the production of various proinflammatory mediators and ultimately cellular injury, leading to the various vascular sequelae of sepsis. This review will focus on the signaling pathways initiated by LPS binding to the TLR4 receptor in endothelial cells and the coordinated regulation of this pathway.

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“…Stimulation of TLR signaling activates IRAK kinases, MAPK, and NF-kB signaling pathways 26 and is associated with BTK and PKC activity. 25,27 Human B-CLL and SMZL cells express numerous TLRs, i.e., TLR1, TLR2, TLR6, TLR7, TLR9, and TLR10. 7,28,29 Engagement of these receptors with their respective ligands leads to activation or proliferation of CLL, 28,29 and SMLZ 7 cells.…”

Section: Surface Expression Of Adhesion Molecules Can Be Modulated Inmentioning

confidence: 99%

The splenic marginal zone shapes the phenotype of leukemia B cells and facilitates their niche-specific retention and survival

et al. 2017

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Microenvironmental regulation in lymphoid tissues is essential for the development of chronic lymphocytic leukemia. We identified cellular and molecular factors provided by the splenic marginal zone (MZ), which alter the migratory and adhesive behavior of leukemic cells. We used the Cxcr5 ¡/¡ Em-Tcl1 leukemia mouse model, in which tumor cells are excluded from B cell follicles and instead accumulate within the MZ. Genes involved in MZ B cell development and genes encoding for adhesion molecules were upregulated in MZ-localized Cxcr5 ¡/¡ Em-Tcl1 cells. Likewise, surface expression of the adhesion and homing molecules, CD49d/VLA-4 and CXCR7, and of NOTCH2 was increased. In vitro, exposing Em-Tcl1 cells or human CLL cells to niche-specific stimuli, like B cell receptor-or Toll-like receptor ligands, caused surface expression of these molecules characteristic for a follicular or MZ-like microenvironment, respectively. In vivo, inhibition of VLA-4-mediated adhesion and CXCL13-mediated follicular homing displaced leukemic cells not only from the follicle, but also from the MZ and reduced leukemia progression. We conclude that MZ-specific factors shape the phenotype of leukemic cells and facilitate their niche-specific retention. This strong microenvironmental influence gains pathogenic significance independent from tumor-specific genetic aberrations.

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Involvement of PKCα/β in TLR4 and TLR2 dependent activation of NF-κB

Cited by 110 publications

References 41 publications

PKC‐α controls MYD88‐dependent TLR/IL‐1R signaling and cytokine production in mouse and human dendritic cells

PKC‐α controls MYD88‐dependent TLR/IL‐1R signaling and cytokine production in mouse and human dendritic cells

Lipopolysaccharide signaling in endothelial cells

The splenic marginal zone shapes the phenotype of leukemia B cells and facilitates their niche-specific retention and survival

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