Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Fiorotto, R; Scirpo, R; Trauner, M; Fabris, L; Hoque, R; Spirli, C; Strazzabosco, M.
Loss of CFTR affects biliary epithelium innate immunity and causes TLR4-NF-κB-mediated inflammatory response in mice.
Gastroenterology. 2011; 141(4): 1508.e1- 1508.e5
Doi: 10.1053/j.gastro.2011.06.052
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- Co-Autor*innen der Med Uni Graz
- Trauner Michael
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- Abstract:
- BACKGROUND & AIMS: Loss of function of the cystic fibrosis transmembrane conductance regulator (CFTR) in the biliary epithelium reduces bile flow and alkalinization in patients with cystic fibrosis (CF). Liver damage is believed to result from ductal cholestasis, but only 30% of patients with CF develop liver defects, indicating that another factor is involved. We studied the effects of CFTR deficiency on Toll-like receptor 4 (TLR4)-mediated responses of the biliary epithelium to endotoxins. METHODS: Dextran sodium sulfate (DSS) was used to induce colitis in C57BL/6J-Cftrtm1Unc (Cftr-KO) mice and their wildtype littermates. Ductular reaction and portal inflammation were quantified by keratin-19 and CD45 immunolabeling. Cholangiocytes isolated from wild-type and Cftr-KO mice were challenged with lipopolysaccharide (LPS); cytokine secretion was quantified. Activation of nuclear factor kappa B (NF-kappa B), phosphorylation of TLR4, and activity of Src were determined. HEK-293 that expressed the secreted alkaline phosphatase reporter and human TLR4 were transfected with CFTR complementary DNAs. RESULTS: DSS-induced colitis caused biliary damage and portal inflammation only in Cftr-KO mice. Biliary damage and inflammation were not attenuated by restoring biliary secretion with 24-nor-ursodeoxycholic acid but were significantly reduced by oral neomycin and polymyxin B, indicating a pathogenetic role of gut-derived bacterial products. Cftr-KO cholangiocytes incubated with LPS secreted significantly higher levels of cytokines regulated by TLR4 and NF-kappa B. LPS-mediated activation of NF-kappa B was blocked by the TLR4 inhibitor TAK-242. TLR4 phosphorylation by Src was significantly increased in Cftr-KO cholangiocytes. Expression of wild-type CFTR in the HEK293 cells stimulated with LPS reduced activation of NF-kappa B. CONCLUSIONS: CFTR deficiency alters the innate immunity of the biliary epithelium and reduces its tolerance to endotoxin, resulting in an Src-dependent inflammatory response mediated by TLR4 and NF-kappa B. These findings might be used to develop therapies for CF-associated cholangiopathy.
- Find related publications in this database (using NLM MeSH Indexing)
- Animals -
- Anti-Bacterial Agents - pharmacology
- Antigens, CD45 - metabolism
- Bile Ducts - drug effects
- Cholagogues and Choleretics - pharmacology
- Cholangitis - chemically induced
- Colitis - chemically induced
- Cytokines - metabolism
- Dextran Sulfate -
- Disease Models, Animal -
- Epithelial Cells - drug effects
- HEK293 Cells -
- Humans -
- Immunity, Innate - drug effects
- Inflammation Mediators - metabolism
- Keratin-19 - metabolism
- Lipopolysaccharides - pharmacology
- Mice -
- Mice, Inbred C57BL -
- Mice, Inbred CFTR -
- Mice, Knockout -
- NF-kappa B - metabolism
- Neomycin - pharmacology
- Phosphorylation -
- Polymyxin B - pharmacology
- Time Factors -
- Toll-Like Receptor 4 - genetics
- Transfection -
- Ursodeoxycholic Acid - analogs & derivatives
- src-Family Kinases -
- Find related publications in this database (Keywords)
- Cystic Fibrosis
- TLR4
- Biliary Epithelium
- Src Kinase