Novel insights in the regulation of C C LI8 secretion by monocytes and dendritic cells via cytokines, Toll-like receptors and rheumatoid synovial fluid
نویسندگان
چکیده
B ackground: The T cell attracting chemokine CCL18 is produced by antigen presenting cells and a role for CCLI8 has been suggested in the pathogenesis of a variety of diseases. Rheumatoid arthritis (RA) is one of these conditions, in which abundant CCL18 production is present. Although Th2 cytokines and IL-10 are known to have an effect on CCLI8 production, there are several gaps in our knowledge regarding the exact regulation of CCLI8 secretion, both in general and in RA. In this study we provide new insights in the regulation of CCLI8 secretion by monocytes and dendritic cells. Results: In contrast to a large panel of pro-inflammatory stimuli (IL-I ß, TNF-a, IL-10, IL-13, IL-15, IL-17, IL-I8, IFN-y), T cell mimicking molecules (RANKL, CD40L) o r TLR driven maturation, the anti-inflammatory IL-I0 strongly stimulated DC to secrete CCLI8. On freshly isolated monocytes, CCLI8 secretion was induced by IL-4 and IL-I3, in strong synergy with IL-I0. This synergistic effect could already be observed after only 24 hours, indicating that not only macrophages and dendritic cells, but also monocytes secrete CCLI8 under these stimulatory conditions. A high CCLI8 expression was detected in RA synovial tissue and incubation of monocytes with synovial fluid from RA patients clearly enhanced the effects of IL-4, IL-I3 and IL-I0. Surprisingly, the effect of synovial fluid was not driven by IL-I0 of IL-I3, suggesting the presence of another CCLI8 inducing factor in synovial fluid. C onclusion: In summary, IL-I0 synergistically induces CCLI8 secretion in combination with IL-4 of IL-I3 on monocytes and monocyte derived cells. The effects of IL-I4, IL-I3 and IL-I0 are strongly enhanced by synovial fluid. This synergy may contribute to the high CCLI8 expression in RA. Open Access
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