Cited by 431Immune Response and InflammationGut microbiota and healthGastrointestinal motility and disorders

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Human Intestinal Epithelial Cells Are Broadly Unresponsive to Toll-Like Receptor 2-Dependent Bacterial Ligands: Implications for Host-Microbial Interactions in the Gut

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Melmed, Gil, Thomas, Lisa S, Lee, Nahee, Tesfay, Samuel Y, Lukasek, Katie, Michelsen, Kathrin S, Zhou, Yuehua, Hu, Bing, Arditi, Moshe, Abreu, Maria T·2003·The Journal of Immunology

DOI 10.4049/jimmunol.170.3.1406

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Abstract

Intestinal epithelial cells (IEC) interact with a high density of Gram-positive bacteria and are active participants in mucosal immune responses. Recognition of Gram-positive organisms by Toll-like receptor (TLR)2 induces proinflammatory gene expression by diverse cells. We hypothesized that IEC are unresponsive to Gram-positive pathogen-associated molecular patterns and sought to characterize the functional responses of IEC to TLR2-specific ligands. Human colonic epithelial cells isolated by laser capture microscopy and IEC lines (Caco-2, T84, HT-29) were analyzed for expression of TLR2, TLR6, TLR1, and Toll inhibitory protein (Tollip) mRNA by RT-PCR and quantitative real-time PCR. Response to Gram-positive bacterial ligands was measured by NF-κB reporter gene activation and IL-8 secretion. TLR2 protein expression was analyzed by immunofluorescence and flow cytometry. Colonic epithelial cells and lamina propria cells from both uninflamed and inflamed tissue demonstrate low expression of TLR2 mRNA compared with THP-1 monocytes. IECs were unresponsive to TLR2 ligands including the staphylococcal-derived Ags phenol soluble modulin, peptidoglycan, and lipotechoic acid and the mycobacterial-derived Ag soluble tuberculosis factor. Transgenic expression of TLR2 and TLR6 restored responsiveness to phenol soluble modulin and peptidoglycan in IEC. In addition to low levels of TLR2 protein expression, IEC also express high levels of the inhibitory molecule Tollip. We conclude that IEC are broadly unresponsive to TLR2 ligands secondary to deficient expression of TLR2 and TLR6. The relative absence of TLR2 protein expression by IEC and high level of Tollip expression may be important in preventing chronic proinflammatory cytokine secretion in response to commensal Gram-positive bacteria in the gut.

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Authors: Melmed, G., Thomas, L. S., Lee, N., Tesfay, S. Y., Lukasek, K., Michelsen, K. S., Zhou, Y., Hu, B., Arditi, M., & Abreu, M. T.
Affiliations: Cedars-Sinai Medical Center (US)
Inflammatory Bowel Disease Center, Division of Gastroenterology, Department of Medicine , Los Angeles, CA 90048
Division of Pediatric Infectious Diseases, Department of Pediatrics, Steven Spielberg Pediatric Research Center, Burns and Allen Research Institute , Los Angeles, CA 90048
Corresponding author: Melmed, Gil
Lee, Nahee
Lukasek, Katie
ORCID: Melmed, Gil
Michelsen, Kathrin S
Zhou, Yuehua
Arditi, Moshe
Abreu, Maria T
Venue: The Journal of Immunology
Publisher: Oxford University Press (OUP)
Published: 2003-02-01
Volume: 170
Issue: 3
Pages: 1406-1415
ISSN: 0022-1767 (ISSN-L)
1550-6606
DOI: 10.4049/jimmunol.170.3.1406
OpenAlex: W1902083634
Cited by: 431
References: 103
Citations by year: 2026: 4 · 2025: 3 · 2024: 5 · 2023: 4 · 2022: 7 · 2021: 6 · 2020: 4 · 2019: 12 · 2018: 12 · 2017: 15 · 2016: 11 · 2015: 13 · 2014: 17 · 2013: 20 · 2012: 18
FWCI: 12.15
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: academic.oup.com/pages/standard-publication-reuse-rights (vor)
Locations: The Journal of Immunology (publishedVersion)
PubMed (publishedVersion)
Funders: National Institutes of Health (5k08dk002635-03, 5r29ai040275-02)
National Heart, Lung, and Blood Institute (HL66436, R01HL066436)
National Institute of Allergy and Infectious Diseases (AI-40275, R29 AI52266)
National Institute of Diabetes and Digestive and Kidney Diseases (DK02635)
Topics: Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
Health Sciences › Medicine › Gastroenterology › Gastrointestinal motility and disorders
Keywords: TLR2, intestinal epithelial cells, Gram-positive bacteria, Tollip, TLR6, phenol-soluble modulins, peptidoglycan, lipoteichoic acid, NF-κB activation, IL-8 secretion, commensal bacteria, mucosal immunity, colonic epithelium, lamina propria, inflammatory cytokines
MeSH terms: Bacterial Toxins, Carrier Proteins, Cell Line, Gene Expression Regulation, Humans, Immune Tolerance, Intestinal Mucosa, Ligands, Lipopolysaccharides, Membrane Glycoproteins, Peptidoglycan, Receptors, Cell Surface, RNA, Messenger, Staphylococcus aureus, Staphylococcus epidermidis, Teichoic Acids, Transfection, Tumor Cells, Cultured, Signal Transduction, Transcriptional Activation, Caco-2 Cells, HT29 Cells, Transgenes, Drosophila Proteins, Intracellular Signaling Peptides and Proteins, Toll-Like Receptors, Toll-Like Receptor 1, Toll-Like Receptor 2, Toll-Like Receptor 6

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Human Intestinal Epithelial Cells Are Broadly Unresponsive to Toll-Like Receptor 2-Dependent Bacterial Ligands: Implications for Host-Microbial Interactions in the Gut

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