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First published online 25 October 2005
doi: 10.1242/jcs.02630

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Interferon- selectively increases epithelial permeability to large molecules by activating different populations of paracellular pores

¹ Gut Barrier Group, Injury Research, Salford Royal Hospitals NHS Trust and Faculty of Medicine and Human Sciences, University of Manchester, Clinical Sciences Building, Hope Hospital, Salford, M6 8HD, UK
² Faculty of Life Sciences, University of Manchester, Oxford Road, Manchester, M13 9PT, UK

^* Author for correspondence (e-mail: gwarhurs{at}fs1.ho.man.ac.uk)

Accepted 11 August 2005

Impairment of the gut epithelial barrier by agents such as IFN may play a key role in the pathogenesis of inflammatory disorders by increasing the paracellular penetration of luminal macromolecules, potentially including bacterial antigens. Owing to limitations of current paracellular probes, little is known about the precise functional changes induced by IFN and how these relate to the development of increased macromolecular permeability. Here we investigate how IFN modulates this pathway in T84 monolayers using a novel profiling technique that resolves different populations of paracellular pores by simultaneous analysis of 24 permeability probes of defined molecular size. Two types of functional pore present in control monolayers, an abundant restrictive pore with a radius of 4.5 Å and a much larger but infrequent, non-restrictive pore, were differentially regulated by IFN. Incubation with IFN dose-dependently and reversibly increased the frequency of the non-restrictive pores while having no significant effect on the restrictive component. Cytokine-induced increases in ß, the descriptor of the non-restrictive pore, correlated closely with increased permeability to large molecules (10 kDa) including E. coli-derived lipopolysaccharide, but not small (0.182 kDa) molecules. This effect was associated with changes in expression of the tight junction proteins occludin and claudin-1. These data suggest that IFN selectively increases the transepithelial flux of large molecules by activating specific pathways within the junctional pore. One hypothesis is that this process may be activated in the early stages of the inflammatory response, facilitating the passage of large and potentially antigenic molecules across the gut without gross disruption of the barrier to small molecules.

Key words: Inflammation, Cytokine, Tight junction, Intestine, Epithelial

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