title: Protection from fluorescein isothiocyanate-induced fibrosis in IL-13-deficient, but not IL-4-deficient, mice results from impaired collagen synthesis by fibroblasts.
abstract: Intratracheal injection of FITC results in acute lung injury and progresses to fibrosis by day 21 postchallenge. In response to FITC, BALB/c mice produce IL-4 and IL-13 in the lung. To investigate whether IL-4 and/or IL-13 were important profibrotic mediators in this model, we examined the fibrotic response to FITC in mice that were genetically deficient in IL-4 (IL-4(-/-)), IL-13 (IL-13(-/-)), or IL-4 and IL-13 combined (IL-4/13(-/-)). Baseline levels of collagen were similar in all mice. In response to FITC, both BALB/c and IL-4(-/-) mice developed fibrosis, whereas the IL-13(-/-) and IL-4/13(-/-) mice were significantly protected, as measured by total lung collagen levels and histology. Total leukocyte recruitment to the lung was similar in all four strains of mice when measured on days 7, 14, and 21 post-FITC. BALB/c mice showed prominent eosinophilia on day 7 that was absent in IL-4(-/-), IL-13(-/-), and IL-4/13(-/-) mice, suggesting that eosinophilia is not necessary for development of a fibrotic response. There were no significant differences in the percentages of any other leukocytes analyzed between the genotypes. Similarly, protection in IL-13(-/-) mice was not associated with alterations in cytokine or eicosanoid profiles. Interestingly, TGF-beta1 production was not reduced in IL-13(-/-) mice. Analyses of fibroblasts isolated from the four genotypes demonstrated that although there were similar numbers of fibroblasts present in cultures of lung minces, fibroblasts from IL-13-deficient strains have reduced basal and stimulated levels of collagen production. IL-13Ralpha1 expression increases on fibroblasts during fibrotic responses in vivo, and IL-13 increases collagen synthesis in fibroblasts. Thus, IL-13 mediates its profibrotic actions through direct effects on fibroblast production of extracellular matrix.
authors.affiliation: Department of Internal Medicine, Graduate Program in Immunology, Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Jill E
authors.initials: JE
authors.lastname: Kolodsick
authors.forename: Galen B
authors.initials: GB
authors.lastname: Toews
authors.forename: Claudia
authors.initials: C
authors.lastname: Jakubzick
authors.forename: Cory
authors.initials: C
authors.lastname: Hogaboam
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Moore
authors.forename: Andrew
authors.initials: A
authors.lastname: McKenzie
authors.forename: Carol A
authors.initials: CA
authors.lastname: Wilke
authors.forename: Cara J
authors.initials: CJ
authors.lastname: Chrisman
authors.forename: Bethany B
authors.initials: BB
authors.lastname: Moore
mesh_terms: D000818:Animals; D002452:Cell Count; D003094:Collagen / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D016207:Cytokines / Q000096:biosynthesis; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D016650:Fluorescein-5-isothiocyanate / Q000633:toxicity*; D020022:Genetic Predisposition to Disease; D005838:Genotype; D007249:Inflammation / Q000139:chemically induced / Q000235:genetics / Q000276:immunology / Q000473:pathology; D018793:Interleukin-13 / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics; D053661:Interleukin-13 Receptor alpha1 Subunit; D015847:Interleukin-4 / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D011657:Pulmonary Eosinophilia / Q000139:chemically induced / Q000235:genetics / Q000276:immunology; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D018123:Receptors, Interleukin / Q000096:biosynthesis / Q000235:genetics; D053660:Receptors, Interleukin-13; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology; D053773:Transforming Growth Factor beta1
chemical_list: D016207:Cytokines; C508183:Il13ra1 protein, mouse; D018793:Interleukin-13; D053661:Interleukin-13 Receptor alpha1 Subunit; D018123:Receptors, Interleukin; D053660:Receptors, Interleukin-13; C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D015847:Interleukin-4; D003094:Collagen; D016650:Fluorescein-5-isothiocyanate