Basic-alimentary tractInterferon γ Induces Translocation of Commensal Escherichia coli Across Gut Epithelial Cells via a Lipid Raft--Mediated Process
Section snippets
Materials
Recombinant human IFN-γ (104 IU/μg) was purchased from R&D Systems (Abingdon, UK). Monoclonal anti-occludin (OC-3F10) and polyclonal anti-claudin 1 antibodies were obtained from Zymed Laboratories Inc (San Francisco, CA). Goat anti-mouse and anti-rabbit horseradish peroxidase (HRP)-conjugated antibodies were purchased from Bio-Rad (Hemel Hempstead, UK). Fluorescein isothiocyanate-labeled goat anti-mouse was obtained from Sigma-Aldrich (Poole, UK). [14C]Mannitol (56 mCi/mmol) was purchased from
Results
Initial studies investigated the correlation between translocation of E coli C25 and loss of paracellular integrity in T84 colonic cells in response to the proinflammatory cytokine IFN-γ. Exposure to basolateral IFN-γ for 48 hours caused an increase in paracellular permeability in T84 monolayers, as judged by a loss of TEER and increased permeability to the paracellular probe LY (Figure 1A). These effects were dose dependent, and both variables showed significant changes at 10 IU/mL IFN-γ, with
Discussion
There is strong evidence that a loss of intestinal barrier function mediated by cytokines and other cellular factors is an early event in the pathogenesis of several disorders ranging from sepsis and multiple organ failure to inflammatory bowel disease.10 The hypothesis is that increased paracellular permeability mediated by the disruption of tight junctions allows increased mucosal penetration by luminal bacteria and bacterial antigens that then initiate or prolong an inflammatory response.
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Supported by the Medical Research Council, United Kingdom, and the Digestive Disorders Foundation.