Enteroendocrine cells express functional Toll-like receptors

Abstract

Intestinal epithelial cells (IECs) provide a physical and immunological barrier against enteric microbial flora. Toll-like receptors (TLRs), through interactions with conserved microbial patterns, activate inflammatory gene expression in cells of the innate immune system. Previous studies of the expression and function of TLRs in IECs have reported varying results. Therefore, TLR expression was characterized in human and murine intestinal sections, and TLR function was tested in an IEC line. TLR1, TLR2, and TLR4 are coexpressed on a subpopulation of human and murine IECs that reside predominantly in the intestinal crypt and belong to the enteroendocrine lineage. An enteroendocrine cell (EEC) line demonstrated a similar expression pattern of TLRs as primary cells. The murine EEC line STC-1 was activated with specific TLR ligands: LPS or synthetic bacterial lipoprotein. In STC-1 cells stimulated with bacterial ligands, NF-κB and MAPK activation was demonstrated. Furthermore, the expression of TNF and macrophage inhibitory protein-2 were induced. Additionally, bacterial ligands induced the expression of the anti-inflammatory gene transforming growth factor-β. LPS triggered a calcium flux in STC-1 cells, resulting in a rapid increase in CCK secretion. Finally, conditioned media from STC-1 cells inhibited the production of nitric oxide and IL-12 p40 by activated macrophages. In conclusion, human and murine IECs that express TLRs belong to the enteroendocrine lineage. Using a murine EEC model, a broad range of functional effects of TLR activation was demonstrated. This study suggests a potential role for EECs in innate immune responses.

Review: Enteroendocrine cells: Neglected players in gastrointestinal disorders?

“…In the same cell line, the TLR4 ligand lipopolysaccharide (LPS) induced the phosphorylation of ERK1/2 and MAPK and activated NF-B activation, the pivotal downstream signaling target of TLR occupancy. STC-1 exposure to LPS also triggered a calcium flux and induced the expression of the proinflammatory cytokine TNF and the anti-inflammatory cytokine TGF-, in conjunction with increased in CCK secretion [Bogunovic et al 2007]. Similar results have been shown by Palazzo et al with TLR 5 and 9 also evident [Palazzo et al 2007].…”

GLP-1R Agonists Modulate Enteric Immune Responses Through the Intestinal Intraepithelial Lymphocyte GLP-1R

“…Furthermore, bacterial-derived products such as LPS and flagellin independently modulated expression of genes encoding peptide hormones and multiple ligands and receptors important for the immune response in LCC-18 enteroendocrine cells (32). Conversely, receptors for vasoactive intestinal peptide and pituitary adenylate cyclase-activating peptide have been localized to intestinal IELs (33), whereas Toll-like receptors are expressed on enteroendocrine cells, and Toll-like receptor activation by bacterial products promotes secretion of cholecystokinin from gut endocrine cells (34). Considerable evidence attests to the importance of inflammation and innate immunity in the control of metabolism (35,36); however, few studies have examined whether IELs play a role in the development and/or treatment of experimental models of type 2 diabetes or obesity.…”

Epigenetic Control of the Host Gene by Commensal Bacteria in Large Intestinal Epithelial Cells

“…This observation indicates that the TLR4 gene is highly methylated in some IEC population but not in another IEC population. Immunohistochemical and mRNA analyses have shown that TLR4 is expressed predominantly in the crypt IECs and expressed less abundantly in the villus IECs (15)(16)(17)(18), suggesting the possibility that the status of TLR4 gene methylation is different between crypt and villus IECs. To compare DNA methylation in the 5Ј region of the TLR4 gene between differentiated IECs at the villi and undifferentiated IECs at the crypts, SIECs were fractionated into two populations (Fr1 and Fr2) depending on their differentiation stage.…”