Gene-environment interactions in inflammatory bowel disease
|PhD ceremony:||Ms A. (Anouk) Regeling|
|When:||October 08, 2014|
|Supervisors:||prof. dr. K.N. (Klaas Nico) Faber, prof. dr. G. Dijkstra|
|Where:||Academy building RUG|
|Faculty:||Medical Sciences / UMCG|
Crohn’s disease (CD) and ulcerative colitis (UC) are autoimmune chronic inflammatory disorders of the intestine that are collectively known as inflammatory bowel diseases (IBDs). They originate in an exaggerated inflammatory response to gut luminal contents, caused by an inaccurate response to environmental factors due to the specific genetic makeup of the individual. Cigarette smoking is known to be beneficial for UC, but detrimental for CD. In this thesis, we aimed to identify smoke-induced mechanisms that can explain the dichotomy in UC and CD. We found that cigarette smoking protects intestinal epithelial cells and T-cells against inflammation-induced apoptosis. This generalized effect of cigarette smoke may lead to mucosal healing in UC, but at the same time further impair proper T-cell termination in CD. To extend our search for genes/proteins responsible for the smoke-induced anti-apoptotic signaling, we found that smoke dose-dependently enhanced the expression of heat shock protein HSPA6 and that HSPA6 physically interacts with and stabilizes the anti-apoptotic protein, Bcl-XL. Furthermore, we found that HSPA6 resides in an UC susceptibility locus. These results reveal a potential mechanism in the smoke-dependent effect on UC. It remains to be determined which smoke-contained component(s) are responsible for the induction of HSPA6 and contribute to the anti-apoptotic effect of cigarette smoking and potential protection against colitis.