Abstract
In Crohn’s Disease (CD) and ulcerative colitis (UC), the major manifestations of inflammatory bowel disease (IBD), genetically predisposed individuals develop chronic intestinal inflammation in response to environmental stimuli, which are mainly derived from luminal flora. Intestinal responses to luminal flora breaching the intestinal barrier require cytokine-regulated activation of elements of innate and acquired immunity, leading to a targeted and contained inflammatory response. Recent population-based genetic analyses have identified polymorphisms in specific genes relevant to pathways critical for inflammatory signalling and cellular response to stress as carrying increased risk for the development of either CD or UC. Specifically, key mediators of apoptosis and autophagy are implicated in the genetic vulnerability to IBD. Patients with IBD have a compromise of their intestinal barrier integrity, as do their first-degree relatives even in the absence of clinical disease, underscoring the critical nature of barrier integrity in the prevention of aberrant immune responses to intestinal flora. Here we explore the relationships between two of the key proinflammatory cytokines mediating intestinal inflammation in IBD, TNF-α and IFNγ, and the mechanisms by which they regulate epithelial apoptosis and intestinal barrier. Specifically we review factors regulating the balance between pro- and antiapoptotic stimuli resulting from the activation of NF-κB and Aktdependent signalling by proinflammatory cytokines, as well as the influence of oxygen tension and nutritional factors on these pathways.
Highlights
The Role of Tissue Responses to Intestinal MicrofloraThe appropriate acquisition and containment of luminal bacterial flora is essential for normal development of both intestinal morphology [11,12] and barrier [13,14], yet luminal flora are critical triggers of inflammatory responses in experimental models of intestinal inflammation [15,16,17] and inflammatory bowel disease (IBD) [18,19]
In Crohn’s Disease (CD) and ulcerative colitis (UC), the major manifestations of inflammatory bowel disease (IBD), genetically predisposed individuals develop chronic intestinal inflammation in response to environmental stimuli, which are mainly derived from luminal flora
IFNγ has been extensively studied in models of IBD, and gene polymorphisms in these mediators or their downstream receptors and signaling pathways have been linked to an increased propensity for IBD, with IFN-γ signaling linked to UC [9] while polymorphisms in the tumor necrosis factor-α (TNF-α) pathway are linked to CD [10]
Summary
The appropriate acquisition and containment of luminal bacterial flora is essential for normal development of both intestinal morphology [11,12] and barrier [13,14], yet luminal flora are critical triggers of inflammatory responses in experimental models of intestinal inflammation [15,16,17] and IBD [18,19]. Bacterial products activate complex combinations of receptors (Pattern Recognition Receptors, PRRs), such as members of the membrane-associated Toll-like Receptor (TLR) [12] and cytosolic Nucleotide Oligomerization Domain (NOD) receptor (NLR) families, which constitute cellular mechanisms for recognition of molecular patterns consistent with non-self [20, 21] Individual members of these receptor families are differentially localized, both within individual cells and along the axis of the intestinal crypt [22,23]. Their combined signaling responses to the presence of invading bacteria or their products determine whether the end result is effective bacterial killing and cell repair, or cell death, necessitating epithelial restitution and proliferation by the surrounding cells [23].
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