Commensal-Associated Molecular Patterns Induce Selective Toll-Like Receptor-Trafficking from Apical Membrane to Cytoplasmic Compartments in Polarized Intestinal Epithelium

Cario, Elke; Brown, Dennis; McKee, Mary; Lynch-Devaney, Kathryn; Gerken, Guido; Podolsky, Daniel K.

doi:10.1016/s0002-9440(10)64360-x

Cited by 277 publications

(218 citation statements)

References 38 publications

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“…TLR2 is known to be upregulated in response to peptidoglycan, lipoteichoic acid, 29 and bacterial lipoproteins 30 or LPS. TLR4 is activated by the LPS of Gram-negative bacteria 31 and LY96 is a protein associated with this receptor. The expression of these two TLR after H. pylori infection has been well documented in the literature.…”

Section: Discussionmentioning

confidence: 99%

Gene expression profiling in human gastric mucosa infected with Helicobacter pylori

et al. 2007

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Pathogenic mechanisms associated with Helicobacter pylori infection enhance susceptibility of the gastric epithelium to carcinogenic conversion. We have characterized the gene expression profiles of gastric biopsies from 69 French Caucasian patients, of which 43 (62%) were infected with H. pylori. The bacterium was detected in 27 of the 42 antral biopsies examined and in 16 of the 27 fundic biopsies. Infected biopsies were selected for the presence of chronic active gastritis, in absence of metaplasia and dysplasia of the gastric mucosa. Infected antral and fundic biopsies exhibited distinct transcriptional responses. Altered responses were linked with: (1) the extent of polymorphonuclear leukocyte infiltration, (2) bacterial density, and (3) the presence of the virulence factors vacA, babA2, and cagA. Robust modulation of transcripts associated with Toll-like receptors, signal transduction, the immune response, apoptosis, and the cell cycle was consistent with expected responses to Gram-negative bacterial infection. Altered expression of interferon-regulated genes (IFITM1, IRF4, STAT6), indicative of major histocompatibility complex (MHC) II-mediated and Th1-specific responses, as well as altered expression of GATA6, have previously been described in precancerous states. Upregulation of genes abundantly expressed in cancer tissues (UBD, CXCL13, LY96, MAPK8, MMP7, RANKL, CCL18) or in stem cells (IFITM1 and WFDC2) may reveal a molecular switch towards a premalignant state in infected tissues. Tissue microarray analysis of a large number of biopsies, which were either positive or negative for the cag-A virulence factor, when compared to each other and to noninfected controls, confirmed observed gene alterations at the protein level, for eight key transcripts. This study provides 'proof-of-principle' data for identifying molecular mechanisms driving H. pylori-associated carcinogenesis before morphological evidence of changes along the neoplastic progression pathway. Modern Pathology (2007) 20, 974-989;

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Section: Discussionmentioning

confidence: 99%

Gene expression profiling in human gastric mucosa infected with Helicobacter pylori

et al. 2007

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“…We hypothesized that IEC are poorly responsive to Gram-positive bacterial cell wall components and other TLR2 ligands. Studies have demonstrated that IEC express TLR2 mRNA but the functional significance of these findings are unclear (71)(72)(73). A recent study using immunohistochemistry demonstrated that lamina propria macrophages express TLR2 and that expression increases with inflammation (74).…”

Section: Human Intestinal Epithelial Cells Are Broadly Unresponsive Tmentioning

confidence: 99%

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

Melmed¹,

Thomas²,

Lee³

et al. 2003

The Journal of Immunology

395

281

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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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“…This finding is in line with the fact that toll-like receptors on immune and epithelial cells can recognize specific bacterial components from dead cells [27]. Despite viability being a requirement of a probiotic per the World Health Organization definition, use of attenuated probiotics could be advantageous due to compliance with regulatory demands, which include microbiological stability, as well as leading to a longer shelf-life of the final product.…”

Section: Discussionmentioning

confidence: 61%

Ex vivo anti-inflammatory effects of probiotics for periodontal health

Schmitter

Fiebich²,

Fischer

et al. 2018

Journal of Oral Microbiology

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Background: Probiotic bacteria with anti-inflammatory properties have the potential to be of therapeutic benefit in gingivitis.Objective: To evaluate the effects of potential probiotic strains on inflammatory mediators involved in early gingivitis using an ex vivo inflammation model.Methods: Strains were screened in viable and attenuated forms for effects on bacterial lipopolysaccharide (LPS)-stimulated release of interleukins (IL)-1β, -6 and -8, tumor necrosis factor-α, prostaglandin E2 and 8-isoprostane from human primary monocytes, and then, if anti-inflammatory effects were shown, on IL-1β-stimulated release of inflammatory mediators from primary gingival fibroblasts. Lead strains were evaluated for optimal dosing, batch-to-batch variation and functional consistency in toothpaste.Results: Twenty-one of 73 strains showed anti-inflammatory effects in monocytes; of which, seven showed effects in both viable and attenuated forms. Seven of 14 strains showed effects in fibroblasts. Strains Lactobacillus paracasei LPc-G110(SYBIO-15) and Lactobacillus plantarum GOS42(SYBIO-41) induced statistically significant dose-dependent reductions in the release of multiple inflammatory mediators from monocytes, which were consistent across batches. Viable L. paracasei LPc-G110 tooth paste significantly reduced IL-6, IL-8 and prostaglandin E2 release from monocytes versus placebo.Conclusion: Strains L. paracasei LPc-G110 and L. plantarum GOS42 have potential for use as probiotics in oral care products to reduce gingival inflammation.

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Commensal-Associated Molecular Patterns Induce Selective Toll-Like Receptor-Trafficking from Apical Membrane to Cytoplasmic Compartments in Polarized Intestinal Epithelium

Cited by 277 publications

References 38 publications

Gene expression profiling in human gastric mucosa infected with Helicobacter pylori

Gene expression profiling in human gastric mucosa infected with Helicobacter pylori

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

Ex vivo anti-inflammatory effects of probiotics for periodontal health

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