Cutting Edge: Peripheral Neuropeptides Attract Immature and Arrest Mature Blood-Derived Dendritic Cells

Dunzendorfer, Stefan; Kaser, Arthur; Meierhofer, Christian; Tilg, Herbert; Wiedermann, Christian J.

doi:10.4049/jimmunol.166.4.2167

Cited by 95 publications

(87 citation statements)

References 31 publications

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“…Hence, we wondered whether FTY720 might modulate chemokine receptor-driven DC migration. DC were allowed to migrate into nitrocellulose filters using RANTES and SDF-1a as stimulators [23]. Immature FTY720-and Comparative flow cytometric analysis of FTY720-treated DC, FTY720-P-treated DC and control DC.…”

Section: Resultsmentioning

confidence: 99%

The immunomodulator FTY720 interferes with effector functions of human monocyte‐derived dendritic cells

et al. 2005

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The potent immunomodulator FTY720 elicits immunosuppression via acting on sphingosine 1-phosphate receptors (S1PR), thereby leading to an entrapment of lymphocytes in the secondary lymphoid tissue. To elucidate the potential in vitro effects of this drug on human monocyte-derived DC, we used low nanomolar therapeutic concentrations of FTY720 and phosphorylated FTY720 (FTY720-P) and investigated their influence on DC surface marker expression, protein levels of S1PR and DC effector functions: antigen uptake, chemotaxis, cytokine production, allostimulatory and Thpriming capacity. We report that both FTY720 and FTY720-P reduce chemotaxis of immature and mature DC. Mature DC generated in the presence of FTY720 or FTY720-P showed an impaired immunostimmulatory capacity and reduced IL-12 but increased IL-10 production. T cells cultured in the presence of FTY720-or FTY720-P-treated DC showed an altered cytokine production profile indicating a shift from Th1 toward Th2 differentiation. In treated immature and mature DC, expression levels for two S1PR proteins, S1P 1 and S1P 4, were reduced. We conclude that in vitro treatment with FTY720 affects DC features that are essential for serving their role as antigen-presenting cells. This might represent a new aspect of the overall immunosuppressive action of FTY720 and makes DC potential targets of further sphingolipid-derived drugs.

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Section: Resultsmentioning

confidence: 99%

The immunomodulator FTY720 interferes with effector functions of human monocyte‐derived dendritic cells

et al. 2005

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“…First-strand cDNA was synthesized from 1 g of total RNA using a mixture of oligo(dT) [12][13][14][15][16][17][18] and random hexamer primers and Superscript Reverse Transcriptase (Invitrogen Life Technologies). For amplification, the qPCR Mastermix Plus for SYBR Green I without UNG (Eurogentec) was used to detect accumulation of PCR products during cycling on an Applied Biosystems 7300 cycler.…”

Section: Analysis Of Cytokine Mrna and Protein Productionmentioning

confidence: 99%

“…Importantly, CGRP also mediates distinct anti-inflammatory and immunosuppressive activities and, therefore, may play a role in neuroimmunological communication. CGRP modulates the adhesion and migration of immune cells including T cells, eosinophilic granulocytes, and dendritic cells (DC) (15)(16)(17). Stimulation of DC with CGRP reduces the expression of MHC class II and costimulatory proteins, augments the production of IL-10, and inhibits the Ag-presenting capacity of these cells (18 -20).…”

mentioning

confidence: 99%

Negative Regulation of TLR Responses by the Neuropeptide CGRP Is Mediated by the Transcriptional Repressor ICER

Harzenetter

Novotny

Gais

et al. 2007

The Journal of Immunology

104

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Communication between the nervous and immune systems involves the release of neuropeptides, such as calcitonin gene-related peptide (CGRP), from sensory nerves during inflammation. CGRP may inhibit the activities of both innate and adaptive immune cells, but the molecular pathways underlying this function are largely unknown. In this study, we identify CGRP as a potent inhibitor of TLR-stimulated production of inflammatory mediators, such as TNF-α and CCL4, by murine dendritic cells. Inhibition of TLR responses was independent of IL-10 and did not involve perturbation of canonical TLR signaling, including activation of MAPK and NF-κB. Instead, the inhibitory activity of CGRP was mediated by the cAMP/protein kinase A pathway leading to rapid up-regulation of the transcriptional repressor, inducible cAMP early repressor (ICER). Ectopically expressed ICER directly repressed the LPS-stimulated activity of a synthetic Tnf promoter, as well as TNF-α protein production driven by the endogenous promoter. Inhibition of dendritic cell gene expression by CGRP was associated with the presence of a composite cAMP response element/κB promoter element. In a murine model of endotoxemia, CGRP markedly attenuated serum TNF-α levels, and this effect was associated with the up-regulation of ICER. Together, these results establish a novel pathway for the negative regulation of TLR responses through the nervous system that critically involves induction of the transcriptional repressor ICER by the neuropeptide CGRP.

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“…Studies have shown that binding of neuropeptides to specific seven transmembrane domain G protein-coupled receptors expressed in various types of immune cells can activate or suppress different immune functions such as cytokine production (3), dendritic cell (DC) 4 maturation (4), Th2 cell polarization (5), and chemotaxis (6,7). These features and their implication in several inflammatory and autoimmune diseases have led to the development of receptorselective agonist and antagonist for the treatment of several diseases (8).…”

mentioning

confidence: 99%

Urotensin II is a New Chemotactic Factor for UT Receptor-Expressing Monocytes

Segain

Rolli–Derkinderen

Gervois

et al. 2007

The Journal of Immunology

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Urotensin II (U-II), a vasoactive cyclic neuropeptide which activates the G protein-coupled receptor UT receptor, exerts various cardiovascular effects and may play a role in the pathophysiology of atherosclerosis. In this study, we report that the UT receptor is expressed and functional on human PBMC and rat splenocytes. PBMC surface expression of the UT receptor was mainly found in monocytes and NK cells, also in a minority of B cells, but not in T cells. Stimulation of monocytes with LPS increased UT receptor mRNA and protein expression. Cloning and functional characterization of the human UT receptor gene promoter revealed the presence of NF-κB-binding sites involved in the stimulation of UT receptor gene expression by LPS. Activation of the UT receptor by U-II induced chemotaxis with maximal activity at 10 and 100 nM. This U-II effect was restricted to monocytes. Analysis of the signaling pathway involved indicated that U-II-mediated chemotaxis was related to RhoA and Rho kinase activation and actin cytoskeleton reorganization. The present results thus identify U-II as a chemoattractant for UT receptor-expressing monocytes and indicate a pivotal role of the RhoA-Rho kinase signaling cascade in the chemotaxis induced by U-II.

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Cutting Edge: Peripheral Neuropeptides Attract Immature and Arrest Mature Blood-Derived Dendritic Cells

Cited by 95 publications

References 31 publications

The immunomodulator FTY720 interferes with effector functions of human monocyte‐derived dendritic cells

The immunomodulator FTY720 interferes with effector functions of human monocyte‐derived dendritic cells

Negative Regulation of TLR Responses by the Neuropeptide CGRP Is Mediated by the Transcriptional Repressor ICER

Urotensin II is a New Chemotactic Factor for UT Receptor-Expressing Monocytes

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