Type I interferons maintain Foxp3 expression and T-regulatory cell functions under inflammatory conditions in mice.

BACKGROUND & AIMS: Foxp3(+) T-regulatory cells (Tregs) maintain intestinal homeostasis under conditions of continuous challenge with inflammatory microbes. However, plasticity of the Treg population under certain conditions has been reported; Foxp3(+) Tregs can be converted to Foxp3(-) CD4(+) T cells. METHODS: We used mice with a T cell-induced colitis model to study the regulatory role of type I interferons (IFNs) in adaptive immunity. We transferred CD4(+)CD45RB(hi) (RB(hi)) T cells, with or without CD4(+)CD45RB(lo) CD25(+) T cells, from wild-type or IFN-αßR(-/-) mice into Rag1(-/-) recipients. We analyzed induction of colitis by flow cytometry, confocal microscopy, and enzyme-linked immunosorbent assay and reverse-transcription polymerase chain reaction analyses. IFN-αßR(-/-)Rag(-/-) mice were given injections of recombinant IFN-α following transfer of IFN-αßR(-/-) RB(hi) T cells and CD4(+)Foxp3(+) cells from Foxp3-eGFP mice. RESULTS: Signaling by type I IFNs was required for maintenance of Foxp3 expression and the suppressive activity of Tregs in mice. Transfer of CD4(+)CD45RB(lo)CD25(+) Tregs from IFN-αßR(-/-) mice did not prevent T-cell induction of colitis in mice. Foxp3 expression by Tregs transferred from IFN-αßR(-/-) mice was significantly lower than that of Tregs from wild-type mice. Administration of recombinant IFN-α reduced T cell-mediated colitis by increasing the number of Foxp3(+) Tregs and their suppressive functions. CONCLUSIONS: Type I IFNs regulate intestinal homeostasis by maintaining Foxp3 expression on Tregs in colons of mice under inflammatory conditions.

Signal transducer and activator of transcription 3 (STAT3) protein suppresses adenoma-to-carcinoma transition in Apcmin/+ mice via regulation of Snail-1 (SNAI) protein stability.

STAT3 was recently reported to suppress tumor invasion in Apc(min)(/+) mice. We investigated the mechanisms by which STAT3 inhibits intestinal epithelial tumors using Apc(min)(/+)/Stat3(IEC-KO) mice (intestinal epithelial cell (IEC)-specific deletion of STAT3 in the Apc(min)(/+) background) to determine the role of STAT3 in carcinogenesis in vivo as well as colorectal cancer cell lines in vitro. To inhibit invasion of IEC tumors, STAT3 functions as a molecular adaptor rather than a transcription factor. Accordingly, the tumors in Apc(min)(/+)/Stat3(IEC-KO) mice undergo adenoma-to-carcinoma transition and acquire an invasive phenotype. Similarly, STAT3 knockdown in a colorectal cell line enhances IEC invasion. We demonstrate that STAT3 down-regulates SNAI (Snail-1) expression levels and hence suppresses epithelial-mesenchymal transition of colorectal cancer cells. Mechanistically, STAT3 facilitates glycogen synthase kinase (GSK) 3ß-mediated degradation of SNAI by regulating phosphorylation of GSK3ß. Our data identified a new role for STAT3 in the adenoma-to-carcinoma sequence of intestinal tumors.