Document Detail

Therapeutic efficacy of Tyro3, Axl, and Mer tyrosine kinase agonists in collagen-induced arthritis.
MedLine Citation:
PMID:  23203851     Owner:  NLM     Status:  MEDLINE    
OBJECTIVE: Hyperactivation of innate immunity by Toll-like receptors (TLRs) can contribute to the development of autoinflammatory or autoimmune diseases. This study evaluated the activation of Tyro3, Axl, Mer (TAM) receptors, physiologic negative regulators of TLRs, by their agonists, growth arrest-specific protein 6 (GAS-6) and protein S, in the prevention of collagen-induced arthritis (CIA).
METHODS: Adenoviruses overexpressing GAS-6 and protein S were injected intravenously or intraarticularly into mice during CIA. Splenic T helper cell subsets from intravenously injected mice were studied by flow cytometry, and the knee joints of mice injected intravenously and intraarticularly were assessed histologically. Synovium from mice injected intraarticularly was evaluated for cytokine and suppressor of cytokine signaling (SOCS) expression.
RESULTS: Protein S significantly reduced ankle joint swelling when overexpressed systemically. Further analysis of knee joints revealed a moderate reduction in pathologic changes in the joint and a significant reduction in the number of splenic Th1 cells when protein S was overexpressed systemically. Local overexpression of GAS-6 decreased joint inflammation and joint pathology. Protein S treatment showed a similar trend of protection. Consistently, GAS-6 and protein S reduced cytokine production in the synovium. Moreover, levels of messenger RNA for interleukin-12 (IL-12) and IL-23 were reduced by GAS-6 and protein S treatment, with a corresponding decrease in the production of interferon-γ and IL-17. TAM ligand overexpression was associated with an increase in SOCS-3 levels, which likely contributed to the amelioration of arthritis.
CONCLUSION: This study provides the first evidence that TAM receptor stimulation by GAS-6 and protein S can be used to ameliorate arthritis when applied systemically or locally. TAM receptor stimulation limits proinflammatory signaling and adaptive immunity. This pathway provides a novel strategy by which to combat rheumatoid arthritis.
B T van den Brand; S Abdollahi-Roodsaz; E A Vermeij; M B Bennink; O J Arntz; C V Rothlin; W B van den Berg; F A J van de Loo
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Arthritis and rheumatism     Volume:  65     ISSN:  1529-0131     ISO Abbreviation:  Arthritis Rheum.     Publication Date:  2013 Mar 
Date Detail:
Created Date:  2013-02-26     Completed Date:  2013-04-24     Revised Date:  2014-03-07    
Medline Journal Info:
Nlm Unique ID:  0370605     Medline TA:  Arthritis Rheum     Country:  United States    
Other Details:
Languages:  eng     Pagination:  671-80     Citation Subset:  AIM; IM    
Copyright Information:
Copyright © 2013 by the American College of Rheumatology.
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MeSH Terms
Adenoviridae / genetics
Arthritis, Experimental / genetics,  pathology,  therapy*
Cytokines / genetics,  metabolism
Genetic Therapy / methods
Injections, Intra-Articular
Intercellular Signaling Peptides and Proteins / genetics*,  metabolism
Knee Joint / metabolism,  pathology
Mice, Inbred DBA
Protein S / genetics*,  metabolism
Proto-Oncogene Proteins / agonists*,  genetics,  metabolism
Receptor Protein-Tyrosine Kinases / agonists*,  genetics,  metabolism
Severity of Illness Index
Signal Transduction / immunology
Suppressor of Cytokine Signaling Proteins / genetics,  metabolism
Synovial Membrane / metabolism,  pathology
Th1 Cells / immunology,  pathology
Grant Support
Reg. No./Substance:
0/Cytokines; 0/Intercellular Signaling Peptides and Proteins; 0/Protein S; 0/Proto-Oncogene Proteins; 0/Socs3 protein, mouse; 0/Suppressor of Cytokine Signaling Proteins; 0/growth arrest-specific protein 6; EC protein, mouse; EC Protein-Tyrosine Kinases; EC protein, mouse; EC receptor tyrosine kinase

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