New insights into the dichotomous role of innate cytokines in gut homeostasis and inflammation

Abstract

In addition to their well-known role in acute injury and chronic inflammation, "innate" cytokines play an important role in health and the maintenance of normal immune homeostasis. This group includes the prototypic cytokines IL-1 and TNFα, as well as several other members belonging to the IL-1 and TNF family, such as IL-18, IL-33, IL-36-38, and TL1A. The dichotomous role of these cytokines has been best characterized in the intestine where innate cytokines may play both a protective and a pro-inflammatory role, depending upon the immmunological status of the host or the type and phase of the inflammatory process. This new information has produced novel pathogenetic hypotheses that have important translational implications both in regard to the prevention and treatment of chronic intestinal inflammation, including Crohn's disease and ulcerative colitis, the two major forms of inflammatory bowel disease. This review will discuss and summarize current data regarding the role of IL-1, TNFα, and their family members in regulating gut mucosal homeostasis and chronic intestinal inflammation.

Figure 1

Mechanisms of intestinal homeostasis. Protection against the enormous load of luminal bacterial content is accomplished through the application of sequential mucosal checkpoints (indicated with the red-cross circles). These checkpoints are organized into three distinct but highly overlapping barriers. The mechanical barrier sustains the physical separation between intraluminal microorganisms and the gut epithelial lining. The antimicrobial barrier consists of nature peptides which act as physical antibiotics against those bacteria that achieve a close contact to the epithelium. Finally, the immunological barrier handles the occasional microbial intruders by efficient intracellular recognition and processing and by regulating the presentation of intraluminal antigens in a manner that leads to the generation of anti-inflammatory/regulatory responses. Both the innate and adaptive arms of immunity are involved in the regulation of this mucosal “immunostat” function. Dashed lines enclose the elements participating in each barrier and demonstrate the overlap between them. APC: antigen-presenting cell.

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.