title: Myofibroblast keratinocyte growth factor reduces tight junctional integrity and increases claudin-2 levels in polarized Caco-2 cells.
abstract: The colonic epithelium is composed of a polarized monolayer sheathed by a layer of pericryptal myofibroblasts (PCMFs). We mimicked these cellular compartments in vitro to assess the effects of paracrine-acting PCMF-derived factors on tight junction (TJ) integrity, as measured by transepithelial electrical resistance (TER). Coculture with 18Co PCMFs, or basolateral administration of 18Co conditioned medium, significantly reduced TER of polarized Caco-2 cells. Among candidate paracrine factors, only keratinocyte growth factor (KGF) reduced Caco-2 TER; basolateral KGF treatment led to time- and concentration-dependent increases in claudin-2 levels. We also demonstrate that amphiregulin (AREG), produced largely by Caco-2 cells, increased claudin-2 levels, leading to epidermal growth factor receptor-mediated TER reduction. We propose that colonic epithelial TJ integrity can be modulated by paracrine KGF and autocrine AREG through increased claudin-2 levels. KGF-regulated claudin-2 induction may have implications for inflammatory bowel disease, where both KGF and claudin-2 are upregulated.
authors.affiliation: Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors.forename: Tae Il
authors.initials: TI
authors.lastname: Kim
authors.forename: Emily J
authors.initials: EJ
authors.lastname: Poulin
authors.forename: Elliot
authors.initials: E
authors.lastname: Blask
authors.forename: Raghida
authors.initials: R
authors.lastname: Bukhalid
authors.forename: Robert H
authors.initials: RH
authors.lastname: Whitehead
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Franklin
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Coffey
mesh_terms: D066258:Amphiregulin; D018938:Caco-2 Cells; D002450:Cell Communication; D045744:Cell Line, Tumor; D002463:Cell Membrane Permeability; D049109:Cell Proliferation; D062446:Claudin-2 / Q000378:metabolism*; D017077:Culture Media, Conditioned; D066255:EGF Family of Proteins; D017097:Electric Impedance; D066246:ErbB Receptors / Q000378:metabolism; D051523:Fibroblast Growth Factor 7 / Q000378:metabolism*; D006023:Glycoproteins / Q000378:metabolism*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000378:metabolism / Q000502:physiology*; D008024:Ligands; D058628:Myofibroblasts / Q000502:physiology*; D019108:Tight Junctions / Q000502:physiology*
chemical_list: C587848:AREG protein, human; D066258:Amphiregulin; D062446:Claudin-2; D017077:Culture Media, Conditioned; D066255:EGF Family of Proteins; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D008024:Ligands; D051523:Fibroblast Growth Factor 7; D066246:ErbB Receptors