Document Detail

Inhibition of IL-10 receptor function in alveolar macrophages by Toll-like receptor agonists.
MedLine Citation:
PMID:  14764735     Owner:  NLM     Status:  MEDLINE    
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.
Stefan Fernandez; Purnima Jose; Margarita G Avdiushko; Alan M Kaplan; Donald A Cohen
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Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Journal of immunology (Baltimore, Md. : 1950)     Volume:  172     ISSN:  0022-1767     ISO Abbreviation:  J. Immunol.     Publication Date:  2004 Feb 
Date Detail:
Created Date:  2004-02-06     Completed Date:  2004-06-15     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  2985117R     Medline TA:  J Immunol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2613-20     Citation Subset:  AIM; IM    
Department of Microbiology, University of Kentucky Medical Center, Lexington, KY 40536, USA.
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MeSH Terms
Adaptor Proteins, Signal Transducing
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
Lipopolysaccharides / metabolism,  pharmacology
Macrophage Activation / drug effects,  immunology
Macrophages, Alveolar / drug effects,  immunology*,  metabolism*
Membrane Glycoproteins / agonists*,  metabolism,  physiology*
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
Reg. No./Substance:
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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