Negative Regulation of TLR Responses by the Neuropeptide CGRP Is Mediated by the Transcriptional Repressor ICER
| Autor: | Marit D. Harzenetter, Petra Gais, Alexander Novotny, Carlos A. Molina, Felicitas Altmayr, Bernhard Holzmann |
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| Rok vydání: | 2007 |
| Předmět: |
Lipopolysaccharides
MAPK/ERK pathway CAMP-Responsive Element Modulator Transcription Genetic Calcitonin Gene-Related Peptide Immunology Response element Down-Regulation Repressor Calcitonin gene-related peptide Biology Cell Line Cyclic AMP Response Element Modulator Mice Cyclic AMP Animals Humans Immunology and Allergy education Protein kinase A Mice Knockout education.field_of_study Tumor Necrosis Factor-alpha Toll-Like Receptors Dendritic Cells Dendritic cell Molecular biology Endotoxemia Cell biology Mice Inbred C57BL Repressor Proteins Female Tumor necrosis factor alpha Receptors Calcitonin Gene-Related Peptide |
| Zdroj: | The Journal of Immunology. 179:607-615 |
| ISSN: | 1550-6606 0022-1767 |
| DOI: | 10.4049/jimmunol.179.1.607 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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