ArticlePloS one2015
Lipopolysaccharide (LPS)-Induced Biliary Epithelial Cell NRas Activation Requires Epidermal Growth Factor Receptor (EGFR).
Article in PloS one, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers.
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Who cites it
30 citing papers in PubMed.
- Pathogen-Specific Regulation of Renin-Angiotensin System Genes in Epithelial Cells: A Comparative Study of SARS-CoV-2 Spike Protein N-Terminal Domain Fragment and Bacterial Lipopolysaccharide.Pathogens (Basel, Switzerland) · 2026Article
- Proof-of-concept study: APOE4 brain endothelial cells as a phenotypic compound screen.Alzheimer's research & therapy · 2026Article
- EGFR activation in cholangiocytes promotes extrahepatic bile duct regeneration after injury.Hepatology communications · 2025Article
- The EGFR Signaling Pathway Is Involved in the Biliary Intraepithelial Neoplasia Associated with Liver Fluke Infection.Pathogens (Basel, Switzerland) · 2025Article
- Article
- The Role of Inflammation in Cholestatic Liver Injury.Journal of inflammation research · 2023Review
- Tenascin-C in fibrosis in multiple organs: Translational implications.Seminars in cell & developmental biology · 2022Review
- Lipopolysaccharide acting via toll-like receptor 4 transactivates the TGF-β receptor in vascular smooth muscle cells.Cellular and molecular life sciences : CMLS · 2022Article
- Increased amphiregulin expression by CD4Clinical & translational immunology · 2022Article
- Article
- Suppression of systemic inflammation and signs of acute and chronic cholangitis by multi-kinase inhibitor 1-(4-Cl-benzyl)-3-chloro-4-(CF3-phenylamino)-1H-pyrrole-2,5-dione.Molecular and cellular biochemistry · 2021Article
- Senescent cholangiocytes release extracellular vesicles that alter target cell phenotype via the epidermal growth factor receptor.Liver international : official journal of the International Association for the Study of the Liver · 2020Article
- Kupffer Cells Regulate Natural Killer Cells Via the NK group 2, Member D (NKG2D)/Retinoic Acid Early Inducible-1 (RAE-1) Interaction and Cytokines in a Primary Biliary Cholangitis Mouse Model.Medical science monitor : international medical journal of experimental and clinical research · 2020Article
- Article
- The transcription factor ETS1 promotes apoptosis resistance of senescent cholangiocytes by epigenetically up-regulating the apoptosis suppressor BCL2L1.The Journal of biological chemistry · 2019Article
- Clonorchis sinensis excretory-secretory products increase malignant characteristics of cholangiocarcinoma cells in three-dimensional co-culture with biliary ductal plates.PLoS pathogens · 2019Article
- Primary Sclerosing Cholangitis: A Concise Review of Diagnosis and Management.Digestive diseases and sciences · 2019Review
- Metabolomic Profiling of Portal Blood and Bile Reveals Metabolic Signatures of Primary Sclerosing Cholangitis.International journal of molecular sciences · 2018Article
- Neutrophils Promote Amphiregulin Production in Intestinal Epithelial Cells through TGF-β and Contribute to Intestinal Homeostasis.Journal of immunology (Baltimore, Md. : 1950) · 2018Article
- Primary Sclerosing Cholangitis, Part 1: Epidemiology, Etiopathogenesis, Clinical Features, and Treatment.Gastroenterology & hepatology · 2018Article
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Authors and funding
4 authors.
Funding
Abstract
Cholangiocytes (biliary epithelial cells) actively participate in microbe-induced proinflammatory responses in the liver and contribute to inflammatory and infectious cholangiopathies. We previously demonstrated that cholangiocyte TLR-dependent NRas activation contributes to proinflammatory/ proliferative responses. We test the hypothesis that LPS-induced activation of NRas requires the EGFR. SV40-transformed human cholangiocytes (H69 cells), or low passage normal human cholangiocytes (NHC), were treated with LPS in the presence or absence of EGFR or ADAM metallopeptidase domain 17 (TACE) inhibitors. Ras activation assays, quantitative RT-PCR, and proliferation assays were performed in cells cultured with or without inhibitors or an siRNA to Grb2. Immunofluorescence for phospho-EGFR was performed on LPS-treated mouse samples and specimens from patients with primary sclerosing cholangitis, primary biliary cirrhosis, hepatitis C, and normal livers. LPS-treatment induced an association between the TLR/MyD88 and EGFR/Grb2 signaling apparatus, NRas activation, and EGFR phosphorylation. NRas activation was sensitive to EGFR and TACE inhibitors and correlated with EGFR phosphorylation. The TACE inhibitor and Grb2 depletion prevented LPS-induced IL6 expression (p<0.05) and proliferation (p<0.01). Additionally, cholangiocytes from LPS-treated mouse livers and human primary sclerosing cholangitis (PSC) livers exhibited increased phospho-EGFR (p<0.01). Moreover, LPS-induced mouse cholangiocyte proliferation was inhibited by concurrent treatment with the EGFR inhibitor, Erlotinib. Our results suggest that EGFR is essential for LPS-induced, TLR4/MyD88-mediated NRas activation and induction of a robust proinflammatory cholangiocyte response. These findings have implications not only for revealing the signaling potential of TLRs, but also implicate EGFR as an integral component of cholangiocyte TLR-induced proinflammatory processes.
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