Production of TNF-α in macrophages activated by T cells, compared with lipopolysaccharide, uses distinct IL-10-dependent regulatory mechanism.
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.
Kennedy Institute of Rheumatology Division, University of Oxford, London W6 8LH, United Kingdom.
Gideon
G
Agbanoma
Ching
C
Li
Darren
D
Ennis
Andrew C
AC
Palfreeman
Lynn M
LM
Williams
Fionula M
FM
Brennan
D001172:Arthritis, Rheumatoid / Q000276:immunology; D006801:Humans; D007249:Inflammation; D016753:Interleukin-10 / Q000276:immunology*; D008070:Lipopolysaccharides; D008213:Lymphocyte Activation / Q000276:immunology*; D008264:Macrophages / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000276:immunology
D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10