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Intestinal myofibroblasts in innate immune responses of the intestine
Open accessAbstract
Background & aims Intestinal myofibroblasts are known to respond to inflammatory signals and may play a role in Crohn's disease-associated fibrosis. However, putative involvement by myofibroblasts in innate immune responses as part of intestinal host defense has not been characterized. We therefore analyzed expression and regulation of toll-like receptors (TLRs) in colonic human myofibroblasts (CCD-18) and primary human colonic myofibroblasts in comparison with human lung myofibroblasts (CCD-37).Methods Expression of TLRs (1-10) and NOD 1 and 2 was assessed before and after stimulation with either lipopolysaccharide (LPS) or lipoteichoic acid (LTA) by using a custom microarray, reverse-transcription polymerase chain reaction, Northern blot and Western blot analysis, and immunohistochemistry. Activation of signaling pathways, translocation of p65, and secretion of interleukin (IL)-8 were determined.Results Messenger RNAs encoding for TLR1-9, as well as NOD1 and NOD2, were amplified from cultured and primary human intestinal myofibroblasts. After stimulation with LPS or LTA, a 1.5-4.2-fold up-regulation of TLRs (2, 3, 4, 6, 7) and elements of the signaling cascade (MyD88, TIR domain-containing adapter protein [TIRAP]) was observed. CCD-18 and CCD-37 cells expressed TLR 2 and 4 protein, which were located primarily on the cell membrane. Stimulation with LTA or LPS resulted in activation of the mitogen-activated protein kinases pathway, nuclear translocation of p65, and significantly increased IL-8 secretion.Conclusions Bacterial components directly activate intestinal myofibroblasts expressing TLRs. These cells may therefore participate in innate immune responses by sensing and responding to bacterial products that have penetrated into the subepithelial compartment.
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“‘Dysbiosis’, defined as an altered disease-associated microbiome, has been shown to increase with the severity of NASH in both rodents and in humans. This is paralleled and closely related to increased intestinal permeability, bacterial translocation into the portal system and activation of pro-inflammatory pathways.148”
From Understanding the cellular interactome of non-alcoholic fatty liver disease (2022) · cites this paper as [148]
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“The downstream kinase IRAK4 controlled pericyte myofibroblast conversion in vitro and pharmacological inhibition of MyD88 signaling with an IRAK4 inhibitor reduced fibrosis by attenuating tissue injury in vivo167”
From Fibrosis: from mechanisms to medicines (2020) · cites this paper as [167]
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“In the kidney, pericytes, a myofibroblast precursor, activate a TLR2/TLR4/MyD88-dependent proinflammatory program in response to tissue injury167”
From Fibrosis: from mechanisms to medicines (2020) · cites this paper as [167]
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Metadata
- Authors
- Otte, J.-M., Rosenberg, I. M., & Podolsky, D. K.
- Affiliations
- Harvard University (US)
- Corresponding author
- Podolsky, Daniel K
- ORCID
- Podolsky, Daniel K
- Venue
- Gastroenterology
- Publisher
- Elsevier BV
- Published
- 2003-06
- Volume
- 124
- Issue
- 7
- Pages
- 1866-1878
- ISSN
- 0016-5085 (ISSN-L)
- OpenAlex
- W1984107869
- Cited by
- 242
- References
- 63
- Citations by year
- 2026: 3 · 2025: 6 · 2024: 7 · 2023: 5 · 2022: 6 · 2021: 9 · 2020: 11 · 2019: 10 · 2018: 15 · 2017: 7 · 2016: 6 · 2015: 17 · 2014: 12 · 2013: 11 · 2012: 16
- FWCI
- 4.00
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Gastroenterology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK 433-51, R01 DK 60049, R01DK060049, P30DK043351)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Health Sciences › Medicine › Gastroenterology › Inflammatory Bowel Disease
- Health Sciences › Medicine › Gastroenterology › Gastrointestinal motility and disorders
- Keywords
- intestinal myofibroblasts, innate immunity, Toll-like receptors, NOD1, NOD2, lipopolysaccharide, lipoteichoic acid, MyD88, TIRAP, MAPK signaling, p65 nuclear translocation, interleukin-8, colonic myofibroblasts, lung myofibroblasts, bacterial sensing
- MeSH terms
- Cells, Cultured, Colon, Fibroblasts, Humans, Immunity, Innate, Intestinal Mucosa, Lipopolysaccharides, Membrane Glycoproteins, Receptors, Cell Surface, RNA, Messenger, Teichoic Acids, Inflammatory Bowel Diseases, Interleukin-8, Reverse Transcriptase Polymerase Chain Reaction, Oligonucleotide Array Sequence Analysis, Mitogen-Activated Protein Kinases, Toll-Like Receptors, Toll-Like Receptor 1, Toll-Like Receptor 2
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