Document Detail


Production of TNF-α in Macrophages Activated by T Cells, Compared with Lipopolysaccharide, Uses Distinct IL-10-Dependent Regulatory Mechanism.
MedLine Citation:
PMID:  22219323     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
Previously, we demonstrated that spontaneous TNF-α production by macrophages in rheumatoid arthritis (RA) synovial tissue is largely driven by contact-dependent activation with T cells in that tissue. Whereas abundant IL-10 is present in these RA synovial cultures, it does not adequately control the production of TNF-α. In this study, we have compared the mechanisms involved in IL-10-mediated TNF-α regulation in LPS-stimulated macrophages with macrophages stimulated with activated T cells. We confirm that in LPS-stimulated macrophages the 3' enhancer region of tnf is essential for tnf transcription, and its regulation by IL-10 is dominated by a STAT3-dependent pathway. However, in contrast, we have found that tnf transcription in macrophages stimulated by activated T cells or by RA synovial T cells does not require the 3' enhancer region of tnf, and that its regulation by IL-10 is subsequently altered and clearly is not mediated by a dominant STAT3 pathway. These observations have very important implications for our understanding as to how IL-10 regulates TNF-α production at sites of chronic inflammation, such as the synovial tissue of patients with RA. Furthermore, these distinct IL-10 mechanisms will have bearing upon the identification of potential therapeutic targets in RA synovial macrophages where the activation stimulus is clearly not LPS.
Authors:
Gideon Agbanoma; Ching Li; Darren Ennis; Andrew C Palfreeman; Lynn M Williams; Fionula M Brennan
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-1-4
Journal Detail:
Title:  Journal of immunology (Baltimore, Md. : 1950)     Volume:  -     ISSN:  1550-6606     ISO Abbreviation:  -     Publication Date:  2012 Jan 
Date Detail:
Created Date:  2012-1-5     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  2985117R     Medline TA:  J Immunol     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Affiliation:
Kennedy Institute of Rheumatology Division, University of Oxford, London W6 8LH, United Kingdom (formerly until August 1, 2011, Kennedy Institute of Rheumatology Division, Imperial College London, London W6 8LH).
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