Negative regulation of TLR responses by the neuropeptide CGRP is mediated by the transcriptional repressor ICER

Marit D. Harzenetter, Alexander R. Novotny, Petra Gais, Carlos Molina, Felicitas Altmayr, Bernhard Holzmann

Research output: Contribution to journalArticleResearchpeer-review

64 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)607-615
Number of pages9
JournalJournal of Immunology
Volume179
Issue number1
DOIs
StatePublished - 1 Jul 2007

Fingerprint

Calcitonin Gene-Related Peptide
Neuropeptides
Dendritic Cells
Nervous System
Up-Regulation
Endotoxemia
Response Elements
Cyclic AMP-Dependent Protein Kinases
Interleukin-10
Immune System
Inflammation
Gene Expression
Serum
Proteins

Cite this

Harzenetter, Marit D. ; Novotny, Alexander R. ; Gais, Petra ; Molina, Carlos ; Altmayr, Felicitas ; Holzmann, Bernhard. / Negative regulation of TLR responses by the neuropeptide CGRP is mediated by the transcriptional repressor ICER. In: Journal of Immunology. 2007 ; Vol. 179, No. 1. pp. 607-615.
@article{2faa9a6e46f448ff89b6b2e25b5781c6,
title = "Negative regulation of TLR responses by the neuropeptide CGRP is mediated by the transcriptional repressor ICER",
abstract = "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.",
author = "Harzenetter, {Marit D.} and Novotny, {Alexander R.} and Petra Gais and Carlos Molina and Felicitas Altmayr and Bernhard Holzmann",
year = "2007",
month = "7",
day = "1",
doi = "10.4049/jimmunol.179.1.607",
language = "English",
volume = "179",
pages = "607--615",
journal = "Journal of Immunology",
issn = "0022-1767",
publisher = "American Association of Immunologists",
number = "1",

}

Negative regulation of TLR responses by the neuropeptide CGRP is mediated by the transcriptional repressor ICER. / Harzenetter, Marit D.; Novotny, Alexander R.; Gais, Petra; Molina, Carlos; Altmayr, Felicitas; Holzmann, Bernhard.

In: Journal of Immunology, Vol. 179, No. 1, 01.07.2007, p. 607-615.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Negative regulation of TLR responses by the neuropeptide CGRP is mediated by the transcriptional repressor ICER

AU - Harzenetter, Marit D.

AU - Novotny, Alexander R.

AU - Gais, Petra

AU - Molina, Carlos

AU - Altmayr, Felicitas

AU - Holzmann, Bernhard

PY - 2007/7/1

Y1 - 2007/7/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=34250853401&partnerID=8YFLogxK

U2 - 10.4049/jimmunol.179.1.607

DO - 10.4049/jimmunol.179.1.607

M3 - Article

VL - 179

SP - 607

EP - 615

JO - Journal of Immunology

JF - Journal of Immunology

SN - 0022-1767

IS - 1

ER -