The Interferon inducible transmembrane protein family (IFITM) includes several highly homologous family members. These genes are involved in multiple molecular and cellular processes, such as, early development, immune response to pathogens, viral restriction, inflammation, malignant transformation, cellular adhesion and cell cycle control. Several findings associate between IFITM genes and pathogenesis in the gastro-intestinal (GI) tract. IFITM2 and IFITM3 genes were shown to be over-expressed in colitis-associated cancers, and in severely inflamed mucosa. Moreover, polymorphisms of the IFITM3 gene were found to be associated with susceptibility to ulcerative colitis.
Our research aims at investigating the molecular pathways governing IFITM genes expression and their role in colitis and in inflammation-related colon cancer.
We showed that wild-type p53 downregulates IFITM2 at the protein level in cancer cell-lines. This regulation is mediated by a DNA-bound form of p53, since it requires the integrity of the DNA binding and the trans-activation domains of p53.
To study the role of IFITM genes in colitis, we induced acute colitis and colitis-associated colon carcinoma by administration of Dextran Sodium Sulfate (DSS) or combination of DSS and Azoxymethane (AOM), respectively, to IFITM3 knocked out mice. We have shown that the absence of a single IFITM3 allele, results in a significantly severe acute colitis and induced tumor incidence and progression, as was evaluated by daily weighting, endoscopic scoring, and histological analysis. Gene expression analysis in colons of naive IFITM3 knocked out mice revealed that these mice predominantly express pro-inflammatory genes, such as IL1-b and IL-6.
Further investigation of the mechanisms, by which IFITM genes are regulated, as wells as their role in GI pathogenicity, are of great importance in attributing to our understanding of the role that immunity plays in complex processes of inflammation and malignancy.
