| TGF-beta regulates T-cell neurokinin-1 receptor internalization and function. | |
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MedLine Citation:
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PMID: 20160079 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Substance P (SP) is a proinflammatory mediator implicated in inflammatory bowel disease (IBD) and other inflammatory states. SP acts by stimulating the neurokinin-1 receptor (NK-1R) on T lymphocytes and other cell types, and regulates these cells in a complex interplay with multiple cytokines. The mechanisms of interaction among these inflammatory mediators are not yet fully understood. Here, we demonstrate that function of the NK-1R, a member of the G protein-coupled receptor (GPCR) superfamily, is modulated by TGF-beta. The latter acts not on a GPCR but via serine-threonine kinase-class receptors. By flow confocal image analysis, we demonstrate that TGF-beta delays SP-induced NK-1R internalization on mucosal T cells isolated from a mouse model of IBD and on granuloma T cells in murine schistosomiasis. Furthermore, luciferase reporter-gene assays revealed that NK-1R stimulation activates the nuclear factor of activated T cell- and activator protein-1-dependent signaling pathways, which are known triggers of effector T-cell cytokine production. TGF-beta markedly increases SP-induced activation of these signaling cascades, suggesting that delayed NK-1R internalization results in enhanced signaling. Providing a link to amplified immune function, SP and TGF-beta, when applied in combination, trigger a strong release of the proinflammatory cytokines IFN-gamma and IL17 from intestinal inflammatory T cells, whereas either agonist alone shows no effect. These observations establish precedent that members of two distinct receptor superfamilies can interact via a previously unrecognized mechanism, and reveal a paradigm of GPCR transregulation that is relevant to IBD and possibly other disease processes. |
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Authors:
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Martin Beinborn; Arthur Blum; Long Hang; Tommy Setiawan; Jonathan C Schroeder; Korynn Stoyanoff; John Leung; Joel V Weinstock |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2010-02-16 |
Journal Detail:
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Title: Proceedings of the National Academy of Sciences of the United States of America Volume: 107 ISSN: 1091-6490 ISO Abbreviation: Proc. Natl. Acad. Sci. U.S.A. Publication Date: 2010 Mar |
Date Detail:
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Created Date: 2010-03-03 Completed Date: 2010-04-16 Revised Date: 2010-09-03 |
Medline Journal Info:
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Nlm Unique ID: 7505876 Medline TA: Proc Natl Acad Sci U S A Country: United States |
Other Details:
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Languages: eng Pagination: 4293-8 Citation Subset: IM |
Affiliation:
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Division of Gastroenterology and Hepatology, Department of Internal Medicine, and Molecular Pharmacology Research Center, Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA 02111, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Cell Line Endocytosis* Flow Cytometry Humans Inflammatory Bowel Diseases / immunology Interleukin-10 / genetics, physiology Mice Mice, Inbred C57BL Microscopy, Confocal Receptors, Neurokinin-1 / immunology*, metabolism Signal Transduction Substance P T-Lymphocytes / immunology* Transforming Growth Factor beta / physiology* |
| Grant Support | |
ID/Acronym/Agency:
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DK058755/DK/NIDDK NIH HHS; DK38327/DK/NIDDK NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Receptors, Neurokinin-1; 0/Transforming Growth Factor beta; 130068-27-8/Interleukin-10; 33507-63-0/Substance P |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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