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  • DKFZ Publication Database  (2)
  • MIGRATION  (2)
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  • DKFZ Publication Database  (2)
  • 1
    Keywords: CELLS ; EXPRESSION ; CELL ; Germany ; KINASE ; MODEL ; PATHWAY ; PATHWAYS ; VOLUME ; DEATH ; transcription ; NF-KAPPA-B ; ACTIVATION ; LIGAND ; INDUCTION ; CONTRAST ; DENDRITIC CELLS ; LYMPH-NODES ; SIGNAL ; FORM ; DIFFERENCE ; CELL-DEATH ; SIGNALING PATHWAYS ; MIGRATION ; ONCOGENE ; ATHEROSCLEROSIS ; immune response ; IMMUNE-RESPONSE ; PERIPHERAL-BLOOD ; CD4(+) T-CELLS ; F ; AUTOIMMUNITY ; CYTOKINE ; PERSISTENT ; NODES ; RE ; STRENGTH ; CD40 LIGAND ; CD40-CD40 LIGAND ; IL-12 PRODUCTION ; PHYSIOLOGICAL STIMULI
    Abstract: Migration to lymph nodes and secretion of cytokines are critical functions of mature dendritic cells (DCs); however, these 2 functions are not necessarily linked. This is the first report showing that quantitative differences in identical signaling pathways determine DC migration and cytokine secretion. Using different polymerized forms of CD40 ligand, we demonstrate that the strength and persistence of CD40 signaling can induce either function. Induction of monocyte-derived DC (MoDC) migration required a weak and transient CD40 signal, whereas strong and persistent CD40 signaling blocked migration and biased toward cytokine secretion. In contrast to MoDCs, CD40 activation of CD1c(+) peripheral blood DCs (PBDCs) induced a nonpersistent, intracellular signaling profile resulting in migratory-type DCs unable to secrete interleukin-12p70 (IL-12p70). Extracellular signal-regulated kinase 1/2 (ERK1/2) and p38K activation synergistically mediated cytokine secretion, whereas migration was enhanced by p38K activation but reduced by persistent ERK1/2 activity. This model of signal strength and persistence also applied when stimulating DCs with intact microbes. Thus, a novel concept emerges in which the type of immune response induced by DCs is tuned by the strength and persistence of DC activating signals. (C) 2004 by The American Society of Hematology
    Type of Publication: Journal article published
    PubMed ID: 15113760
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  • 2
    Keywords: CELLS ; EXPRESSION ; Germany ; INHIBITION ; KINASE ; PATHWAY ; PATHWAYS ; DISTINCT ; DIFFERENTIATION ; TIME ; ACTIVATION ; INFECTION ; CONTRAST ; DENDRITIC CELLS ; SIGNAL ; NUMBER ; SIGNALING PATHWAY ; SIGNALING PATHWAYS ; MIGRATION ; Jun ; INDIVIDUALS ; sensitivity ; ADAPTIVE IMMUNITY ; CYCLIC-AMP ; ORGANIZATION ; signaling ; CYTOKINE ; RE ; secretion ; SOLID TUMORS ; IL-12 PRODUCTION ; LEVEL ; NEGATIVE REGULATION ; PHOSPHATIDYLINOSITOL 3-KINASE ; PERSISTENCE ; function ; Mol Oncol ; VARIABLES ; PROTEIN-KINASE-A ; VARIETIES ; RAF ; CYTOKINE SECRETION ; MIGRATORY CAPACITY
    Abstract: Phenotypic maturation, cytokine secretion, and migration are distinct functional characteristics of dendritic cells (DCs). These functions are independently regulated by a number of extracellular variables, such as type, strength, and persistence of an array of soluble and membrane-bound mediators. Since the exact composition of these variables in response to infection may differ between individuals, the intracellular signaling pathways activated by these extracellular networks may more closely correlate with DC function and predict the course of adaptive immunity. We found that activation of p38 kinase (p38K), extracellular signal-related kinase 1/2 (ERK1/2), and phosphatidylcholine-specific phospholipase C (PC-PLC) enhanced cytokine secretion, whereas p38K, cyclic adenosine monophosphate (cAMP), and PC-PLC enhanced migration. In contrast, phosphatidylinositol 3-kinase (PI3K)/Akt-1 and cAMP inhibited cytokine secretion while ERK1/2 inhibited migration. Migration and cytokine secretion further differed in their sensitivity to inhibition over time. However, although DCs could be manipulated to express migration, cytokine secretion, or both, the level of activation or persistence of intracellular pathway signaling was not predictive. Our results suggest a modular organization of function. We hypothesize that the expression of specific DC functions integrates a large variety of activating and inhibitory variables, and is represented by the formation of a functional unit of molecular networks-the signal response module (SRM). The combined activities of these modules define the functional outcome of DC activation
    Type of Publication: Journal article published
    PubMed ID: 16527899
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