Cytokine Tuning of Intestinal Epithelial Function

Abstract

The intestine serves as both our largest single barrier to the external environment and the host of more immune cells than any other location in our bodies. Separating these potential combatants is a single layer of dynamic epithelium composed of heterogeneous epithelial subtypes, each uniquely adapted to carry out a subset of the intestine's diverse functions. In addition to its obvious role in digestion, the intestinal epithelium is responsible for a wide array of critical tasks, including maintaining barrier integrity, preventing invasion by microbial commensals and pathogens, and modulating the intestinal immune system. Communication between these epithelial cells and resident immune cells is crucial for maintaining homeostasis and coordinating appropriate responses to disease and can occur through cell-to-cell contact or by the release or recognition of soluble mediators. The objective of this review is to highlight recent literature illuminating how cytokines and chemokines, both those made by and acting on the intestinal epithelium, orchestrate many of the diverse functions of the intestinal epithelium and its interactions with immune cells in health and disease. Areas of focus include cytokine control of intestinal epithelial proliferation, cell death, and barrier permeability. In addition, the modulation of epithelial-derived cytokines and chemokines by factors such as interactions with stromal and immune cells, pathogen and commensal exposure, and diet will be discussed.

Keywords: chemokine; cytokine; epithelium; intestine; mucosal immunology.

Figure 1

Cytokines can positively or negatively affect intestinal epithelial barrier integrity by driving or inhibiting critical epithelial cell functions such as proliferation, apoptosis, and appropriate epithelial barrier permeability. These cytokines can be derived from resident innate or adaptive immune cells, infiltrating inflammatory cells, or from intestinal epithelial cells themselves. Abbreviations: T, T cell; B, B cell; ILC, innate lymphoid cell.

Figure 2

Cytokines may promote or inhibit proliferation of intestinal epithelial cells. Interferon (IFN)-γ may induce or limit intestinal epithelial proliferation based on duration of exposure. In addition, specific cytokines may only induce proliferation of certain epithelial subtypes. For example, interleukin (IL)-4 increases tuft cell numbers, IL-13 signaling supports increases in tuft and goblet cells, and IL-33 stimulates the expansion of goblet and Paneth cells.

Figure 3

Cytokines can induce or prevent apoptosis in intestinal epithelial cells. TNF has been shown to either promote or inhibit intestinal epithelial cell apoptosis under different conditions. Abbreviations: IAP, inhibitor of apoptosis protein; IRF1, interferon regulatory factor 1; RIPK1, receptor interacting protein kinase 1; TNF, tumor necrosis factor.

Figure 4

Appropriate permeability of the intestinal epithelium maintains balance between nutrient absorption and pathogen exclusion. Cytokines may reinforce or impair the intestinal barrier by altering permeability of the epithelium. Epithelial tight junction permeability may be increased or decreased by cytokine modification of the expression or localization of tight junction protein components, such as various claudins, occludin, or zonula occludens protein-1 (ZO-1). Cytokines can also drive phosphorylation of myosin light chains, resulting in contraction and opening of tight junctions. Interferon (IFN)-γ increases intercellular adhesion molecule-1 (ICAM-1) expression, and subsequently, ICAM-1-mediated adherence of neutrophils to gut epithelial apical membranes. Neutrophil ligation of ICAM-1 drives the phosphorylation of myosin light-chain kinase (MLCK), resulting in actin reorganization leading to increased paracellular permeability and neutrophil transepithelial migration.

Figure 5

Pathogens, commensal bacteria, and probiotics can increase or diminish the production of cytokines and chemokines by the intestinal epithelium. These interactions may promote or deter immune cell infiltration of the gut, such as by increasing or reducing the production of chemokines, including interleukin (IL)-8 and monocyte chemoattractant protein-1 (MCP-1). In some cases, bacterial interactions with the gut epithelium may instruct the intestinal immune system. For example, intestinal epithelial cells produce thymic stromal lymphopoietin (TSLP) and transforming growth factor-β (TGF-β) 1 in response to commensal bacteria, inducing a tolerogenic phenotype in dendritic cells.