P070 TNFα production by classical monocytes is poorly controlled by IL-10 in patients with IBD

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Background: IL-10 knock-out mice as well as mice with a conditional knock out of the IL-10 receptor (IL-10Rα) limited to myeloid populations develop bacterially-driven colitis. This highlights the role of myeloid cell IL-10 signaling in immunoregulatory responses to intestinal bacteria. In humans, loss-of-function IL-10R mutations cause severe early-onset IBD; these individuals may represent the end of a spectrum in which suboptimal control of myeloid cells by IL-10 leads to gut inflammation. Our aim is to investigate whether monocyte populations from adult onset IBD patients exhibit a diminished response to IL-10 compared with controls.

Methods: LPS-induced TNFα production, STAT3 phosphorylation in the presence or absence of IL-10, as well as IL-10Rα expression, were measured by flow cytometry in well-characterised circulating monocyte subsets from IBD patients and controls.

Results: Intestinal macrophages are replenished from circulating monocytes. Three subsets of human monocytes are described: classical (CD14+CD16-), which by analogy with murine monocyte populations are likely to replenish intestinal macrophages, intermediate (CD14+CD16+), and non-classical (CD14-CD16+), which remain in the circulation. A mean of 78% (SEM ±4.46) of classical and 89% (SEM ±2.39) of intermediate monocytes from healthy donors produced TNFα upon LPS stimulation. This was significantly reduced by 2ng/ml IL-10 in both myeloid populations (p<0.001). The mean reduction of TNFα in classical monocytes (68%; SEM ±5.59) was significantly greater than in intermediate monocytes (43%; SEM ±4.53 (p=0.009)), despite similar STAT3 availability and equivalent IL-10-induced STAT3 phosphorylation. Fewer LPS-stimulated non-classical monocytes produced TNFα (mean of 33%; SEM ±6.24), which was also poorly reduced in response to IL-10 (26%; SEM ±5.87), an outcome which may be explained by relatively low STAT3-availability and poor IL-10-induced STAT3 phosphorylation. Since classical monocytes were well regulated by IL-10, these cells were compared in health and IBD. Despite increased expression of IL-10Rα and IL-10-induced STAT3 phosphorylation, IL-10 was significantly less effective at inhibiting TNFα production by classical monocytes from IBD patients than controls.

Conclusions: TNFα production by intermediate and non-classical monocytes is poorly controlled by IL-10 and may be relevant to inflammation in IL-10-rich environments such as the intestine. However, a sub-optimal response of classical monocytes to IL-10 may also contribute to inflammation in IBD.

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