title: Inflammatory processes have differential effects on claudins 2, 3 and 4 in colonic epithelial cells.
abstract: Claudin proteins comprise a recently described family of tight junction proteins that differentially regulate paracellular permeability. Since other tight junction proteins show alterations in distribution or expression in inflammatory bowel disease (IBD) we assessed expression of claudins (CL) 2, 3 and 4 in IBD. CL 2 was strongly expressed along the inflamed crypt epithelium, whilst absent or barely detectable in normal colon. In contrast, CL 3 and 4 were present throughout normal colonic epithelium and were reduced or redistributed in the diseased surface epithelium. In a T84-cell culture model of the gut barrier, paracellular permeability decreased with time after plating and correlated with a marked decrease in the expression of CL 2. Addition of IFNgamma/TNFalpha led to further decreases in CL 2 and 3, the redistrbution of CL 4 and a marked increase in paracellular permeability. Conversely, IL-13 dramatically increased CL 2, with little effect on CL 3 or 4, but also resulted in increased paracellular permeability. Expression of CL 2 did not correlate with proliferation or junctional reorganisation after calcium ion depletion. Re-expression of CL 2 in response to IL-13 was inhibited by phophatidylinositol 3 kinase inhibitor, LY294002, which also restored the ion permeability to previous levels. CL 2 expression could be stimulated in the absence of IL-13 by activation of phospho-Akt in the phophatidylinositol 3 kinase pathway. These results suggest that INFgamma/TNFalpha and IL-13 have differential effects on CL 2, 3 and 4 in tight junctions, which may lead to increased permeability via different mechanisms.
authors: Division of Infection, Inflammation and Repair, Southampton General Hospital, University of Southampton School of Medicine, Southampton, UK.
authors: Shyam
authors: S
authors: Prasad
authors: Roberto
authors: R
authors: Mingrino
authors: Katri
authors: K
authors: Kaukinen
authors: Katherine L
authors: KL
authors: Hayes
authors: Robert M
authors: RM
authors: Powell
authors: Thomas T
authors: TT
authors: MacDonald
authors: Jane E
authors: JE
authors: Collins
mesh_terms: D001483:Base Sequence; D015153:Blotting, Western; D002455:Cell Division; D002867:Chromones / Q000494:pharmacology; D062465:Claudin-3; D062506:Claudin-4; D057167:Claudins; D003106:Colon / Q000166:cytology / Q000503:physiopathology*; D017931:DNA Primers; D004591:Electrophoresis, Polyacrylamide Gel; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells / Q000502:physiology; D006801:Humans; D007150:Immunohistochemistry; D018836:Inflammation Mediators / Q000502:physiology*; D007371:Interferon-gamma / Q000502:physiology; D018793:Interleukin-13 / Q000037:antagonists & inhibitors / Q000502:physiology; D007413:Intestinal Mucosa / Q000503:physiopathology*; D008565:Membrane Proteins / Q000502:physiology*; D009025:Morpholines / Q000494:pharmacology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology
chemical_list: C491875:CLDN2 protein, human; C568122:CLDN3 protein, human; C568157:CLDN4 protein, human; D002867:Chromones; D062465:Claudin-3; D062506:Claudin-4; D057167:Claudins; D017931:DNA Primers; D004791:Enzyme Inhibitors; D018836:Inflammation Mediators; D018793:Interleukin-13; D008565:Membrane Proteins; D009025:Morpholines; D000081082:Phosphoinositide-3 Kinase Inhibitors; D014409:Tumor Necrosis Factor-alpha; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D007371:Interferon-gamma