期刊
JOURNAL OF IMMUNOLOGY
卷 188, 期 3, 页码 1307-1317出版社
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1100625
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资金
- Arthritis Research UK
- MRC [G0700128] Funding Source: UKRI
- Medical Research Council [G0700128] Funding Source: researchfish
Previously, we demonstrated that spontaneous TNF-alpha 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-alpha. In this study, we have compared the mechanisms involved in IL10-mediated TNF-alpha 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-alpha 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. The Journal of Immunology, 2012, 188: 1307-1317.
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