Notch signaling in differentiation and function of dendritic cells

Cheng, Pingyan; Gabrilovich, Dmitry I.

doi:10.1007/s12026-007-8011-z

Cited by 44 publications

(29 citation statements)

References 108 publications

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“…Maturation of Human DCs-The maturation of DCs often involves the spectrum of cellular signaling events, including TLR2-dependent activation of NOTCH signaling, which is suggested to play an important role in critical cell fate decisions during DC maturation and subsequent priming of effector T cell responses (37,38). In this regard, we and others have previously shown that TLR2 stimulation leads to up-regulation of NOTCH1 and activation of the NOTCH1 signaling pathway by inducing the formation of a cleavage product of NOTCH1 (NICD) as well as robust activation of Jagged1 expression, a NOTCH1 receptor ligand (39 -44).…”

Section: Notch1-pi3k Signaling Dynamics Integrated Into Signaling Cohmentioning

confidence: 99%

Cooperative Regulation of NOTCH1 Protein-Phosphatidylinositol 3-Kinase (PI3K) Signaling by NOD1, NOD2, and TLR2 Receptors Renders Enhanced Refractoriness to Transforming Growth Factor-β (TGF-β)- or Cytotoxic T-lymphocyte Antigen 4 (CTLA-4)-mediated Impairment of Human Dendritic Cell Maturation

Ghorpade

Kaveri

Bayry

et al. 2011

Journal of Biological Chemistry

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Dendritic cells (DCs) as sentinels of the immune system are important for eliciting both primary and secondary immune responses to a plethora of microbial pathogens. Cooperative stimulation of a complex set of pattern-recognition receptors, including TLR2 and nucleotide-binding oligomerization domain (NOD)-like receptors on DCs, acts as a rate-limiting factor in determining the initiation and mounting of the robust immune response. It underscores the need for "decoding" these multiple receptor interactions. In this study, we demonstrate that TLR2 and NOD receptors cooperatively regulate functional maturation of human DCs. Intriguingly, synergistic stimulation of TLR2 and NOD receptors renders enhanced refractoriness to TGF-␤-or CTLA-4-mediated impairment of human DC maturation. Signaling perturbation data suggest that NOTCH1-PI3K signaling dynamics assume critical importance in TLR2-and NOD receptor-mediated surmounting of CTLA-4-and TGF-␤-suppressed maturation of human DCs. Interestingly, the NOTCH1-PI3K signaling axis holds the capacity to regulate DC functions by virtue of PKC␦-MAPK-dependent activation of NF-B. This study provides mechanistic and functional insights into TLR2-and NOD receptor-mediated regulation of DC functions and unravels NOTCH1-PI3K as a signaling cohort for TLR2 and NOD receptors. These findings serve in building a conceptual foundation for the design of improved strategies for adjuvants and immunotherapies against infectious diseases.

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Section: Notch1-pi3k Signaling Dynamics Integrated Into Signaling Cohmentioning

confidence: 99%

Cooperative Regulation of NOTCH1 Protein-Phosphatidylinositol 3-Kinase (PI3K) Signaling by NOD1, NOD2, and TLR2 Receptors Renders Enhanced Refractoriness to Transforming Growth Factor-β (TGF-β)- or Cytotoxic T-lymphocyte Antigen 4 (CTLA-4)-mediated Impairment of Human Dendritic Cell Maturation

Ghorpade

Kaveri

Bayry

et al. 2011

Journal of Biological Chemistry

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“…Notch1 expression and downstream signaling play crucial roles in immune cell differentiation and development (42,43). Although Notch1 is abundantly expressed in DCs, its role in DC crosspriming remains unclear.…”

Section: Discussionmentioning

confidence: 99%

Integrin CD11b Negatively Regulates TLR9-Triggered Dendritic Cell Cross-Priming by Upregulating microRNA-146a

Bai

Qian

et al. 2012

The Journal of Immunology

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Dendritic cells (DCs) play critical roles in cross-priming to induce the CTL response against infection; however, the molecular mechanisms for the regulation of DC cross-priming need to be investigated further, which may help to improve the potency of DC vaccines through engineering modifications. Our previous studies showed that β2 integrin CD11b could control TLR-triggered NK cell cytotoxicity and macrophage inflammatory responses. CD11b is also abundantly expressed in DCs, but it is unknown whether CD11b participates in the regulation of DC cross-priming for the CTL response. Also, because microRNAs (miRNAs) are important regulators of the immune response, it remains unclear whether miRNAs are regulated by CD11b in DCs. In this study, we showed that CD11b deficiency upregulated TLR9-triggered, but not TLR4-triggered, IL-12p70 production in DCs, subsequently promoting DC cross-priming of the CTL response. Further experiments showed that CD11b selectively promoted TLR9-triggered miR-146a upregulation in DCs by sustaining late-phase NF-κB activation. Additionally, Notch1, a known positive regulator of IL-12p70 production in DCs, was confirmed to be directly targeted by miR-146a. miR-146a upregulation and Notch1 repression were determined to be responsible for the reduced IL-12p70 production in TLR9-triggered wild-type DCs compared with that in CD11b-deficient DCs. Therefore, CD11b and downstream miR-146a may be new negative regulators for DC cross-priming by suppressing Notch1 expression and IL-12p70 production. Our data indicate a new mechanism for the regulation of DC cross-priming through integrins and miRNAs.

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“…Both canonical Wnt and Notch signaling pathway is indispensable for stem and progenitor cell fate determination and subsequent differentiation during embryonic development and adult life (42)(43)(44)(45)(46). These two pathways are reciprocally regulated.…”

Section: Discussionmentioning

confidence: 99%

Pleiotrophin Regulates Lung Epithelial Cell Proliferation and Differentiation during Fetal Lung Development via β-Catenin and Dlk1

Weng¹,

Gao

Bhaskaran

et al. 2009

Journal of Biological Chemistry

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The role of pleiotrophin in fetal lung development was investigated. We found that pleiotrophin and its receptor, proteintyrosine phosphatase receptor ␤/, were highly expressed in mesenchymal and epithelial cells of the fetal lungs, respectively. Using isolated fetal alveolar epithelial type II cells, we demonstrated that pleiotrophin promoted fetal type II cell proliferation and arrested type II cell trans-differentiation into alveolar epithelial type I cells. Pleiotrophin also increased wound healing of injured type II cell monolayer. Knockdown of pleiotrophin influenced lung branching morphogenesis in a fetal lung organ culture model. Pleiotrophin increased the tyrosine phosphorylation of ␤-catenin, promoted ␤-catenin translocation into the nucleus, and activated T cell factor/lymphoid enhancer factor transcription factors. Dlk1, a membrane ligand that initiates the Notch signaling pathway, was identified as a downstream target of the pleiotrophin/␤-catenin pathway by endogenous dlk1 expression, promoter assay, and chromatin immunoprecipitation. These results provide evidence that pleiotrophin regulates fetal type II cell proliferation and differentiation via integration of multiple signaling pathways including pleiotrophin, ␤-catenin, and Notch pathways.Fetal lung development is a complex biological process. Rat lung originates from the foregut endoderm as a bifurcation at embryonic day 10 (E10) and undergoes several generations of dichotomous branching morphogenesis to form a respiratory tree thereafter (1). The columnar epithelial cells differentiate into Clara cells and epithelial cells. Although surfactant protein C is detected as early as E13, fetal alveolar epithelial type II cells (fAEC II) 3 are not fully differentiated until E18 when glycogen pool-enriched cells become cuboidal and differentiate into cells containing lamellar bodies. fAEC II can further differentiate and give rise to the alveolar epithelial type I cells (AEC I).The regulation of fetal lung development includes coordinated regulation of molecular pathways as well as reciprocal interactions among mesenchymal cells, epithelial cells, and the extracellular matrix (2). Precise signals from mesenchymal cells regulate lung branching morphogenesis and lead to cell fate determination and the subsequent generation of cell type diversity in the lung epithelium. For example, mesenchymal cells secrete fibroblast growth factor 10 (3, 4). Fibroblast growth factor 10 in turn binds to its receptor, which is located on the surface of epithelial cells. The binding transduces a message to downstream signaling to regulate cell proliferation, differentiation, migration, and branching morphogenesis. Similarly, the epithelial cells also secrete signal molecules to interact with the mesenchyme. Sonic hedgehog (Shh) is growth factor expressed in the developing epithelium. Its receptor, Patched-1 (Ptc), is located on mesenchymal cells. The interaction between Shh and Ptc has been shown to be required for lung bud formation (5). Other growth factors such as pl...

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Notch signaling in differentiation and function of dendritic cells

Cited by 44 publications

References 108 publications

Cooperative Regulation of NOTCH1 Protein-Phosphatidylinositol 3-Kinase (PI3K) Signaling by NOD1, NOD2, and TLR2 Receptors Renders Enhanced Refractoriness to Transforming Growth Factor-β (TGF-β)- or Cytotoxic T-lymphocyte Antigen 4 (CTLA-4)-mediated Impairment of Human Dendritic Cell Maturation

Cooperative Regulation of NOTCH1 Protein-Phosphatidylinositol 3-Kinase (PI3K) Signaling by NOD1, NOD2, and TLR2 Receptors Renders Enhanced Refractoriness to Transforming Growth Factor-β (TGF-β)- or Cytotoxic T-lymphocyte Antigen 4 (CTLA-4)-mediated Impairment of Human Dendritic Cell Maturation

Integrin CD11b Negatively Regulates TLR9-Triggered Dendritic Cell Cross-Priming by Upregulating microRNA-146a

Pleiotrophin Regulates Lung Epithelial Cell Proliferation and Differentiation during Fetal Lung Development via β-Catenin and Dlk1

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