title: Proinflammatory cytokine synthesis by mucosal fibroblasts from mouse colitis is enhanced by interferon-gamma-mediated up-regulation of CD40 signalling.
abstract: Gut mesenchymal fibroblasts form complex phenotypical and functional populations. They participate actively in homeostatic maintenance of the extracellular matrix, epithelial barrier function, repair mechanisms and leucocyte migration. In inflammation, they become activated, change matrix expression and synthesize proinflammatory mediators. Subpopulations of mucosal fibroblasts express CD40 and the aim of this study was to define its role in their proinflammatory function. Stable primary fibroblast lines derived from normal mouse colon and inflamed colon from CD4(+) CD45RB(high)-transplanted SCID mice were used as models to explore the role of mucosal fibroblast CD40 in the inflammatory process. Phenotype correlated with in situ fibroblast phenotype in the tissues of origin. Lines from both sources co-expressed CD40 and Thy1.2 independently of alpha-smooth muscle actin. A subpopulation of CD40(+) fibroblasts from normal colon expressed CD40 at high levels and expression was enhanced by interferon (IFN)-gamma treatment, whereas all CD40(+) fibroblasts from colitis expressed at low levels and expression was unaffected by IFN-gamma treatment. Despite lower-level expression of CD40 by cells from colitis, they secreted constitutively interleukin (IL)-6 and C-C chemokine (CCL)2. Ligation of CD40 enhanced secretion of these mediators and induced secretion of CCL3. CD40 in cells from colitis was more responsive to ligation than CD40 on cells from normal tissue and this sensitivity was amplified selectively by the action of IFN-gamma. We conclude that the inflammatory milieu in colitis induces long-lasting changes in phenotype and proinflammatory function in colonic fibroblasts. In particular, proinflammatory signalling from fibroblast CD40 is amplified synergistically by the Th1 effector T cell cytokine, IFN-gamma.
authors.affiliation: Department of Microbiology and Immunology, Institute of Biomedicine, Gothenburg University, Gothenburg, Sweden. Tanya.karlson@immuno.gu.se
authors.forename: T
authors.initials: T
authors.lastname: De L Karlson
authors.forename: C V
authors.initials: CV
authors.lastname: Whiting
authors.forename: P W
authors.initials: PW
authors.lastname: Bland
mesh_terms: D000818:Animals; D019013:CD40 Antigens / Q000276:immunology* / Q000378:metabolism; D023201:CD40 Ligand / Q000276:immunology; D002460:Cell Line; D003092:Colitis / Q000276:immunology*; D016207:Cytokines / Q000096:biosynthesis*; D005347:Fibroblasts / Q000276:immunology*; D018836:Inflammation Mediators / Q000276:immunology; D007371:Interferon-gamma / Q000276:immunology*; D007413:Intestinal Mucosa / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D015398:Signal Transduction / Q000276:immunology; D015854:Up-Regulation / Q000276:immunology
chemical_list: D019013:CD40 Antigens; D016207:Cytokines; D018836:Inflammation Mediators; D023201:CD40 Ligand; D007371:Interferon-gamma