Inflammatory bowel disease (IBD) consists of two disease entities, Crohn's Disease (CD) and Ulcerative Colitis (UC). Both diseases manifest as chronic, relapsing and remitting bouts of gastrointestinal inflammation. The etiology of these disease, although not completely understood, consists of a complex interplay between genetic alterations rendering increased susceptibility, the gastrointestinal flora, and hyper-responsiveness of the immune system. Tumor necrosis factor (TNF) is a multifunctional cytokine that has been shown to be upregulated in the colon of and systemically in patients with inflammatory bowel disease. Additionally, anti-TNF therapy has proven effective for the treatment of CD. However, TNF has been shown to have divergent roles in the pathogenesis of disease, depending upon the cellular source of secretion, the length of time of production, the local and systemic concentration of the cytokine and the receptor signaling pathway activated. Here we demonstrate that TNF required for protection against acute colitis and enterocytes derived TNF is the determinant for conferring this protection. In addition, the increased inflammation seen in mice with complete Tnf deficiency and enterocyte derived Tnf deficient mice is accompanied by changes in the microbioal flora which could be contributory components of the disease. In contrast, as colitis progresses from acute to chronic, the protective role of TNF is lost and with chronicity, TNF promotes atypical glandular hyperplasia, inflammation, and cancer. Evaluation of the role of TNF from specific cellular sources in the context of colitis associated colon cancer (CAC) revealed disparate roles for TNF in cancer development depending on the cell type secreting the cytokine. Here we show that enterocyte derived TNF promotes CAC, whereas TNF from T cells protects against CAC. These findings highlight the potentially beneficial versus pathogenic effects of TNF in colitis and CAC and underscore the need more evaluation of the current therapeutic practices for IBD patients.
Read
