IL-17a and IL-22 Induce Expression of Antimicrobials in Gastrointestinal Epithelial Cells and May Contribute to Epithelial Cell Defense against Helicobacter pylori

Abstract

Helicobacter pylori colonization of the human stomach can lead to adverse clinical outcomes including gastritis, peptic ulcers, or gastric cancer. Current data suggest that in addition to bacterial virulence factors, the magnitude and types of immune responses influence the outcome of colonization. Specifically, CD4+ T cell responses impact the pathology elicited in response to H. pylori. Because gastritis is believed to be the initiating host response to more detrimental pathological outcomes, there has been a significant interest in pro-inflammatory T cell cytokines, including the cytokines produced by T helper 17 cells. Th17 cells produce IL-17A, IL-17F, IL-21 and IL-22. While these cytokines have been linked to inflammation, IL-17A and IL-22 are also associated with anti-microbial responses and control of bacterial colonization. The goal of this research was to determine the role of IL-22 in activation of antimicrobial responses in models of H. pylori infection using human gastric epithelial cell lines and the mouse model of H. pylori infection. Our data indicate that IL-17A and IL-22 work synergistically to induce antimicrobials and chemokines such as IL-8, components of calprotectin (CP), lipocalin (LCN) and some β-defensins in both human and primary mouse gastric epithelial cells (GEC) and gastroids. Moreover, IL-22 and IL-17A-activated GECs were capable of inhibiting growth of H. pylori in vitro. While antimicrobials were activated by IL-17A and IL-22 in vitro, using a mouse model of H. pylori infection, the data herein indicate that IL-22 deficiency alone does not render mice more susceptible to infection, change their antimicrobial gene transcription, or significantly change their inflammatory response.

301 The psoriasis-associated IL-17A induces and cooperates with IL-36 cytokines to control keratinocyte differentiation and function

“…S5) 14,15 . The functionally relevant induction of AMPs is consistent with studies in other tissues that also reported the induction of AMPs in response to IL-17 cytokines [47][48][49] . Of note is that AMPs also possess signaling functions for various cell types 50 .…”

Inflammation, immunity, and vaccines for Helicobacter pylori infection

“…Th17 cells producing their signature cytokines IL‐17A, IL‐17F, IL‐21, and IL‐22 approached the spotlight as they are linked to inflammation, but also to antimicrobial responses and the control of bacterial colonization. Recently, a synergistic action of IL‐17A and IL‐22 to induce antimicrobials and chemokines such as IL‐8, calprotectin, lipocalin, and β‐defensins in both human and primary mouse gastric epithelial cells and gastroids was proposed . In this study, IL‐22‐ and IL‐17A‐activated gastric epithelial cells were capable of inhibiting growth of H. pylori in vitro.…”

Intestinal epithelial cells: at the interface of the microbiota and mucosal immunity

“…Reciprocally, activated ILC2s secrete IL‐13, which promotes tuft and goblet cell differentiation and parasite clearance . The signature cytokines secreted by Th17 cells (IL‐17A, IL‐17F and IL‐22) can also induce IEC‐mediated AMP secretion and reinforce IEC tight junctions . In addition, production of fibroblast growth factor 2 (FGF2) by Treg cells has recently been shown to synergize with IL‐17 to enhance mechanisms of intestinal epithelial repair .…”