| Inhibition of IL-10 receptor function in alveolar macrophages by Toll-like receptor agonists. | |
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MedLine Citation:
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PMID: 14764735 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Despite an immunosuppressive lung environment, alveolar macrophages (AM) retain the capacity to respond to microorganisms. This report demonstrates that IL-10, constitutively produced by normal alveolar epithelium, stimulates signal transduction through the IL-10R on AM and that IL-10R function can be inhibited by stimulation of Toll-like receptor (TLR) on AM. IL-10 mRNA and protein were constitutively expressed in normal alveolar epithelium of mice, and IL-10R were constitutively expressed on normal murine AM. Stimulation of AM through TLR2, TLR4, or TLR9 was sufficient to inhibit IL-10R signal transduction, including phosphorylation and nuclear translocation of STAT3 transcription factor. Inhibition of IL-10R function by TLRs was not associated with a decrease in IL-10R expression, but did require expression of the myeloid differentiation factor 88 adaptor protein. Continuous exposure of macrophages to IL-10 caused sustained expression of the chemokine receptors CCR1 and CCR5. However, the addition of TLR ligands inhibited IL-10-induced expression of CCR1 and CCR5. Finally, exposure of macrophages to TLR ligands blocked the ability of IL-10 to inhibit the induction of TNF-alpha by C2-ceramide. These findings demonstrate a novel regulatory mechanism that may allow AM to overcome inhibitory effects of constitutive IL-10 in the lungs that may permit a more effective response to pulmonary infections. |
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Authors:
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Stefan Fernandez; Purnima Jose; Margarita G Avdiushko; Alan M Kaplan; Donald A Cohen |
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Publication Detail:
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Type: Comparative Study; Journal Article; Research Support, U.S. Gov't, P.H.S. |
Journal Detail:
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Title: Journal of immunology (Baltimore, Md. : 1950) Volume: 172 ISSN: 0022-1767 ISO Abbreviation: J. Immunol. Publication Date: 2004 Feb |
Date Detail:
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Created Date: 2004-02-06 Completed Date: 2004-06-15 Revised Date: 2007-11-14 |
Medline Journal Info:
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Nlm Unique ID: 2985117R Medline TA: J Immunol Country: United States |
Other Details:
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Languages: eng Pagination: 2613-20 Citation Subset: AIM; IM |
Affiliation:
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Department of Microbiology, University of Kentucky Medical Center, Lexington, KY 40536, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Adaptor Proteins, Signal Transducing Animals Antigens, Differentiation / genetics, physiology Bronchoalveolar Lavage Fluid / chemistry, immunology CpG Islands / immunology DNA-Binding Proteins / antagonists & inhibitors, metabolism Dose-Response Relationship, Immunologic Down-Regulation / genetics, immunology Immunosuppressive Agents / antagonists & inhibitors, pharmacology Interleukin-10 / antagonists & inhibitors, metabolism*, pharmacology Ligands Lipopolysaccharides / metabolism, pharmacology Macrophage Activation / drug effects, immunology Macrophages, Alveolar / drug effects, immunology*, metabolism* Membrane Glycoproteins / agonists*, metabolism, physiology* Mice Mice, Inbred C57BL Mice, Knockout Myeloid Differentiation Factor 88 Oligodeoxyribonucleotides / metabolism, pharmacology Receptors, Cell Surface / agonists*, metabolism, physiology* Receptors, Immunologic / deficiency, genetics, physiology Receptors, Interleukin / antagonists & inhibitors*, biosynthesis, physiology* Receptors, Interleukin-10 STAT3 Transcription Factor Signal Transduction / genetics, immunology Sphingosine / analogs & derivatives*, antagonists & inhibitors, pharmacology Teichoic Acids / metabolism, pharmacology Toll-Like Receptor 2 Toll-Like Receptor 4 Toll-Like Receptors Trans-Activators / antagonists & inhibitors, metabolism |
| Grant Support | |
ID/Acronym/Agency:
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HL57399/HL/NHLBI NIH HHS; HL69459/HL/NHLBI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Adaptor Proteins, Signal Transducing; 0/Antigens, Differentiation; 0/CPG-oligonucleotide; 0/DNA-Binding Proteins; 0/Immunosuppressive Agents; 0/Ligands; 0/Lipopolysaccharides; 0/Membrane Glycoproteins; 0/Myd88 protein, mouse; 0/Myeloid Differentiation Factor 88; 0/N-acetylsphingosine; 0/Oligodeoxyribonucleotides; 0/Receptors, Cell Surface; 0/Receptors, Immunologic; 0/Receptors, Interleukin; 0/Receptors, Interleukin-10; 0/STAT3 Transcription Factor; 0/Stat3 protein, mouse; 0/Teichoic Acids; 0/Toll-Like Receptor 2; 0/Toll-Like Receptor 4; 0/Toll-Like Receptors; 0/Trans-Activators; 123-78-4/Sphingosine; 130068-27-8/Interleukin-10; 56411-57-5/lipoteichoic acid |
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