Polyamines are required for expression of Toll-like receptor 2 modulating intestinal epithelial barrier integrity
Abstract
The Toll-like receptors (TLRs) allow mammalian intestinal epithelium to detect various microbes and activate innate immunity after infection. TLR2 and TLR4 have been identified in intestinal epithelial cells (IECs) as fundamental components of the innate immune response to bacterial pathogens, but the exact mechanism involved in control of TLR expression remains unclear. Polyamines are implicated in a wide variety of biological functions, and regulation of cellular polyamines is a central convergence point for the multiple signaling pathways driving different epithelial cell functions. The current study determined whether polyamines regulate TLR expression, thereby modulating intestinal epithelial barrier function. Depletion of cellular polyamines by inhibiting ornithine decarboxylase (ODC) with alpha-difluoromethylornithine decreased levels of TLR2 mRNA and protein, whereas increased polyamines by ectopic overexpression of the ODC gene enhanced TLR2 expression. Neither intervention changed basal levels of TLR4. Exposure of normal IECs to low-dose (5 microg/ml) LPS increased ODC enzyme activity and stimulated expression of TLR2 but not TLR4, while polyamine depletion prevented this LPS-induced TLR2 expression. Decreased TLR2 in polyamine-deficient cells was associated with epithelial barrier dysfunction. In contrast, increased TLR2 by the low dose of LPS enhanced epithelial barrier function, which was abolished by inhibition of TLR2 expression with specific, small interfering RNA. These results indicate that polyamines are necessary for TLR2 expression and that polyamine-induced TLR2 activation plays an important role in regulating epithelial barrier function.
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Blocking endogenous polyamine production with an ornithine decarboxylase inhibitor negatively affects maintenance, repair, and function of the intestinal epithelium.
“blocking endogenous production of polyamines with a chemical inhibitor of ornithine decarboxylase negatively affects maintenance, repair and function of the intestinal epithelium”
From Understanding the Holobiont: How Microbial Metabolites Affect Human Health and Shape the Immune System (2017) · cites this paper as Chen et al., 2007
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- Authors
- Chen, J., Rao, J. N., Zou, T., Liu, L., Marasa, B. S., Xiao, L., Zeng, X., Turner, D. J., & Wang, J.-Y.
- Affiliations
- Baltimore VA Medical Center (US)
- University of Maryland, Baltimore (US)
- Venue
- American Journal of Physiology-Gastrointestinal and Liver Physiology
- Publisher
- American Physiological Society
- Published
- 2007-09
- Volume
- 293
- Issue
- 3
- Pages
- G568-G576
- ISSN
- 0193-1857 (ISSN-L)
- 1522-1547
- OpenAlex
- W2132690146
- Cited by
- 107
- References
- 56
- Citations by year
- 2026: 4 · 2025: 4 · 2024: 8 · 2023: 9 · 2022: 10 · 2021: 11 · 2020: 4 · 2019: 11 · 2018: 4 · 2017: 5 · 2016: 4 · 2015: 4 · 2014: 3 · 2013: 4 · 2012: 5
- FWCI
- 1.36
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- American Journal of Physiology-Gastrointestinal and Liver Physiology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK061972, (DK-57819, R01DK068491, DK-61972, R01DK057819, DK-68491)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Polyamine Metabolism and Applications
- Health Sciences › Medicine › Gastroenterology › Gastrointestinal motility and disorders
- Keywords
- polyamines, TLR2, TLR4, intestinal epithelial barrier, ornithine decarboxylase, difluoromethylornithine, lipopolysaccharide, innate immunity, epithelial barrier dysfunction, gene expression regulation
- MeSH terms
- Eflornithine, Animals, Enzyme Inhibitors, Epithelial Cells, Humans, Immunity, Innate, Intestinal Mucosa, Lipopolysaccharides, Ornithine Decarboxylase, Permeability, Polyamines, RNA, Messenger, Time Factors, Transfection, Immunity, Mucosal, Caco-2 Cells, RNA Interference, RNA, Small Interfering, Toll-Like Receptor 2, Toll-Like Receptor 4, Rats, Ornithine Decarboxylase Inhibitors
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