2,4 The importance of TNF in disease pathogenesis is underlined by the pronounced clinical improvement induced when anti-TNF antibodies reduce diarrhea, weight loss, and bleeding.4,5 At the mucosal level, anti-TNF antibody treatment enhances mucosal healing with rapid re-epithelialization of ulcerated surfaces. Studies indicate selleck chemicals some (eg, infliximab and adalimumab), but not all (eg, certolizumab), anti-TNF agents induce apoptosis of lamina propria cells, despite all three being able to enhance mucosal healing.6,7 However, it remains unclear whether the effect of anti-TNF on mucosal healing is related to reduced epithelial apoptosis and, if so, through what mechanism. Overproduction of TNF in IBD has potent effects on mucosal adaptive and innate immune responses.

8,9 TNF participates in macrophage activation by enhancing antimicrobial functions.10 In response to TNF, macrophages increase production of reactive nitrosative species, such as nitric oxide (NO?) and its metabolite, peroxynitrite (ONOO?).11 Inducible NO synthase (iNOS) blockade inhibits disease severity and epithelial apoptosis in animal models of IBD.12,13 Data from human IBD studies suggest that NO? and ONOO? stabilize p53 and activate response pathways.14,15 During tumorigenesis, NO?-induced mutations of p53 inactivate tumor suppressor function, with loss of protective effects.16 Thus, TNF-mediated activation of iNOS may be an important pathway for regulating epithelial cell apoptosis during colitis and colitis-induced dysplasia. Understanding TNF receptor signaling is complex and difficult to apply to in vivo systems.

TNF receptor 1 (TNFR1) associates with the TNF receptor�Cassociated death domain, which activates the extrinsic, caspase 8�Clinked pathway of apoptosis.17,18 However, in some systems examined, TNF receptor�Cassociated death domain is dispensable for TNF-induced apoptosis, and cross activation of TNFRl and TNFR2 converges unto common downstream signaling events, resulting in apoptosis mediated by intrinsic (mitochondrial) pathways.17,19 The proliferative zone for intestinal epithelial cells (IECs) resides in lower crypt regions. Cellular proliferation requires enhanced mitochondrial function. Given that epithelial apoptosis in IBD occurs in proliferative crypt epithelial cells, we suspected that pathways involving induction of mitochondrial pathways were used.

In addition, a comprehensive understanding of the role of TNF receptor signaling within the mucosal microenvironment requires that receptor deficiency be restricted to distinct populations Dacomitinib participating in mucosal immune responses. Increased epithelial crypt cell apoptosis commonly occurs in ulcerative colitis (UC) and Crohn’s disease.20,21 Numerous in vitro and in vivo model systems have studied this phenomenon, suggesting that TNF-mediated pathways play key roles in inducing programmed cell death in epithelial crypts.