The anti‐inflammatory IFITM genes ameliorate colitis and partially protect from tumorigenesis by changing immunity and microbiota

Abstract

Inflammation plays pivotal roles in different stages of tumor development. Screening for predisposing genetic abnormalities and understanding the roles these genes play in the crosstalk between immune and cancer cells will provide new targets for cancer therapy and prevention. The interferon inducible transmembrane (IFITM) genes are involved in pathogenesis of the gastrointestinal tract. We aimed at delineating the role of IFITM3 in colonic epithelial homeostasis, inflammation and colitis-associated tumorigenesis using IFITM3-deficient mice. Chemical induction of colitis in IFITM3-deficient mice results in significantly increased clinical signs of inflammation and induction of invasive tumorigenesis. Bone marrow transplantation showed that cells of the hematopoietic system are responsible for colitis deterioration. In these mice, impaired cytokine expression skewed inflammatory response toward pathogenic Th17 with reduced expression of the anti-inflammatory cytokine IL10 during the recovery phase. Intriguingly, mice lacking the entire IFITM locus developed spontaneous chronic colitis from the age of 14 weeks. Sequencing the 16S rRNA of na€ ıve mice lacking IFITM3 gene, or the entire locus containing five IFITM genes, revealed these mice had significant bacterial differences from their wild-type littermates. Our novel results provide strong evidence for the essential role of IFITM genes in ameliorating colitis and colitis-associated tumorigenesis.

The IFITM protein family in adaptive immunity

“…82 IFITM3 deficiency led to exacerbation of chemical-induced colitis, with increased infiltration of macrophages and effector T cells to the colon lamina propria, and biased CD4 + Th differentiation to Th17. 82 That this exacerbated colitis was attributable to cells of the haematopoietic system was confirmed in bone marrow transplantation experiments. Interestingly, IfitmDel À/À mice developed spontaneous chronic colitis, indicating that other IFITM proteins are also protective against colitis, and both Ifitm3 À/À and IfitmDel À/À showed changes in the faecal microbiota.…”

“…Interestingly, IfitmDel À/À mice developed spontaneous chronic colitis, indicating that other IFITM proteins are also protective against colitis, and both Ifitm3 À/À and IfitmDel À/À showed changes in the faecal microbiota. 82…”

Understanding the Physiological Functions of the Host Xenobiotic-sensing Nuclear Receptors PXR and CAR on the Gut Microbiome using Genetically Modified Mice

“…AF12 sp. is an under-characterized microbe, with some literature nding a correlation between higher abundance and lower body weight, although some evidence is con icting [100][101][102][103]. Additionally, AF12 sp.…”

Topology, Antiviral Functional Residues and Mechanism of IFITM1

“…Therefore, the exact topology of IFITMs is still to be investigated. IFITM proteins are involved in the regulation of many activities, such as tumorigenesis [4] and immune signal transduction [5]. Most importantly, it has been reported that IFITM proteins have a broad antiviral spectrum in recent decades.…”