Figure 2.

Dichotomous effects of innate cytokines during homeostatic conditions and IBD. Lamina propria bacterial load may increase either as part of the normal process of intraluminal antigen sampling of commensal microorganisms or following a transient breach in barrier function. The latter may occur as a result of pathogenic infection, external injury (i.e. administration of drugs with intestinal toxicity) or concomitant systemic morbidity. Under such conditions, cells of the innate immune system respond quickly to eliminate the intruding microorganisms by phagocytosis. During this process a vast array of pro-inflammatory cytokines is induced. The cell origins for these cytokines include both monocytes involved in the phagocytosis of bacteria as well as the epithelial cells. These molecules generate an acute inflammatory response which results in the elimination of excessive numbers of bacteria. At the same time certain cytokines, such as TNFα, IL-18 and IL-33 facilitate the repair process, which re-establishes the integrity of the epithelial monolayer. In contrast, during IBD one or more of the homeostatic mechanisms are dysfunctional and several deficiencies may occur. The antimicrobial and epithelial barriers may be inadequate to hold the commensal bacteria separated from the gut-associated immune system of the lamina propria and/or the intracellular processing of bacteria may be impaired and/or the secretion of pro-inflammatory factors may be dysregulated. These points of failure are indicated in the above by the red asterisks. The end result of these defects is the setting of the mucosal immunostat on “inflammation”, which results in the continuous release of pro-inflammatory factors. In this case, several of these factors are secreted by activated lymphocytes and their different cellular origin may impact on their function. For example IL-18 and TNF produced by lymphocytes demonstrate toxicity against the epithelium, further deteriorating the integrity of the epithelial barrier.