title: Physiological importance of various NFκB family members in regulating intestinal responses to injury
Creators: name: Hanedi, Abdalla
Publisher: name: University of Liverpool Repository
Year: 2013

description: As key regulators of cell survival, proliferation and immune responses, the NFκB family of transcription factors, which signal via the classical and alternative activation pathways, play important roles in intestinal physiology. The pro-inflammatory function of the classical NFκB activation pathway has previously been demonstrated in various animal models of intestinal inflammation. Persistent activation of this pathway has also been detected in the colonic mucosa of patients with inflammatory bowel diseases (IBD). Conversely, several studies in transgenic mice have shown that disruption of the classical NFκB activation pathway specifically in intestinal epithelial cells renders these cells more susceptible to undergoing apoptosis and also results in increased susceptibility to developing colitis. However, the specific roles of individual members of the NFκB family and in particular the role of the alternative NFκB activation pathway in regulating the susceptibility of the intestine to apoptosis, inflammation and colitis associated colon cancer have not been well defined. We therefore hypothesised that individual members of the NFκB family of proteins which signal via the classical and alternative activation pathways specifically regulate intestinal epithelial cell proliferation, apoptosis and colonic inflammation, consequently modulating susceptibility to developing inflammation associated colon cancer. Most of these aims were addressed using transgenic mice with germline deletions of c-Rel, NFκB1, and NFκB2, along with their wild-type counterparts. Intestinal epithelial apoptosis was induced using either γ-irradiation or irinotecan administration. Colitis was induced using dextran sulphate sodium (DSS) and colitis associated cancer by a combination of azoxymethane (AOM) and DSS. In vitro studies were performed in HCT116 colon carcinoma cells. Disruption of classical NFκB signalling by deletion of NFκB1 but not c-Rel sensitised intestinal epithelial cells to undergo apoptosis following γ-irradiation and irinotecan administration. Deleting either c-Rel or NFκB1 also exacerbated the severity of experimental acute and chronic DSS-induced colitis in mice. However, only c-Rel-null mice showed an increase in AOM/DSS induced colonic tumours. This was associated with c-Rel, but not NFκB1 deletion resulting in persistent colonic epithelial mitosis and increased crypt regeneration following DNA damage. Disruption of the alternative NFκB activation pathway by either deleting NFκB2 (in vivo) or suppressing its expression (in vitro) also increased the susceptibility of intestinal epithelial cells to undergo apoptosis following DNA damaging stimuli. Conversely and intriguingly however, deleting NFκB2 also protected mice from developing colitis and colitis associated colon cancer. Specific members of the NFκB family therefore play different roles in regulating the intestinal responses to various types of cellular injury. NFκB2 in particular appears to be essential for developing colitis and its associated cancer. Pharmacological inhibition of NFκB2 may therefore be a promising novel therapeutic strategy for IBD, whereas inhibition of c-Rel signalling may increase susceptibility to developing colitis and its associated colon cancer.