Tissue Inhibitor of Metalloproteinase-3 Regulates Inflammation in Human and Mouse Intestine

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"High Expression of the ""A Disintegrin And Metalloprotease"" 19 (ADAM19), a Sheddase for TNF-alpha in the Mucosa of Patients with Inflammatory Bowel Diseases"

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RORGT-expressing tregs drive the growth of colitis-associated colorectal cancer by controlling IL6 in dendritic cells

Chronic inflammation drives colitis-associated colorectal cancer (CAC) in inflammatory bowel disease (IBD). FoxP3+ regulatory T cells (Treg) coexpressing the Th17-related transcription factor ROR\u3b3t accumulate in the lamina propria of IBD patients, where they are thought to represent an intermediate stage of development toward a Th17 proinflammatory phenotype. However, the role of these cells in CAC is unknown. ROR\u3b3t+FoxP3+ cells were investigated in human samples of CAC, and their phenotypic stability and function were investigated in an azoxymethane/dextran sulfate sodium model of CAC using Treg fate-mapping reporter and Treg-specific ROR\u3b3t conditional knockout mice. Tumor development and the intratumoral inflammatory milieu were characterized in these mice. The functional role of CTLA-4 expressed by Tregs and FoxO3 in dendritic cells (DC) was studied in vitro and in vivo by siRNA-silencing experiments. ROR\u3b3t expression identified a phenotypically stable population of tumor-infiltrating Tregs in humans and mice. Conditional ROR\u3b3t knockout mice showed reduced tumor incidence, and dysplastic cells exhibited low Ki67 expression and STAT3 activation. Tumor-infiltrating DCs produced less IL6, a cytokine that triggers STAT3-dependent proliferative signals in neoplastic cells. ROR\u3b3t-deficient Tregs isolated from tumors overexpressed CTLA-4 and induced DCs to have elevated expression of the transcription factor FoxO3, thus reducing IL6 expression. Finally, in vivo silencing of FoxO3 obtained by siRNA microinjection in the tumors of ROR\u3b3t-deficient mice restored IL6 expression and tumor growth. These data demonstrate that ROR\u3b3t expressed by tumor-infiltrating Tregs sustains tumor growth by leaving IL6 expression in DCs unchecked. Cancer Immunol Res; 6(9); 1082-92. \ua92018 AACR