title: Homeostatic role of transforming growth factor-beta in the oral cavity and esophagus of mice and its expression by mast cells in these tissues.
abstract: Transforming growth factor-beta (TGF-beta) is a pleiotropic growth factor; its overexpression has been implicated in many diseases, making it a desirable target for therapeutic neutralization. In initial safety studies, mice were chronically treated (three times per week) with high doses (50 mg/kg) of a murine, pan-neutralizing, anti-TGF-beta antibody. Nine weeks after the initiation of treatment, a subset of mice exhibited weight loss that was concurrent with decreased food intake. Histopathology revealed a unique, nonneoplastic cystic epithelial hyperplasia and tongue inflammation, as well as dental dysplasia and epithelial hyperplasia and inflammation of both the gingiva and esophagus. In an effort to determine the cause of this site-specific pathology, we examined TGF-beta expression in these tissues and saliva under normal conditions. By immunostaining, we found higher expression levels of active TGF-beta1 and TGF-beta3 in normal tongue and esophageal submucosa compared with gut mucosal tissues, as well as detectable TGF-beta1 in normal saliva by Western blot analysis. Interestingly, mast cells within the tongue, esophagus, and skin co-localized predominantly with the TGF-beta1 expressed in these tissues. Our findings demonstrate a novel and restricted pathology in oral and esophageal tissues of mice chronically treated with anti-TGF-beta that is associated with basal TGF-beta expression in saliva and by mast cells within these tissues. These studies illustrate a previously unappreciated biological role of TGF-beta in maintaining homeostasis within both oral and esophageal tissues.
authors.affiliation: Genzyme Corporation, 1 The Mountain Rd., Framingham, MA 01701-9322, USA.
authors.forename: Allison
authors.initials: A
authors.lastname: Vitsky
authors.forename: James
authors.initials: J
authors.lastname: Waire
authors.forename: Robert
authors.initials: R
authors.lastname: Pawliuk
authors.forename: Arden
authors.initials: A
authors.lastname: Bond
authors.forename: Douglas
authors.initials: D
authors.lastname: Matthews
authors.forename: Emily
authors.initials: E
authors.lastname: Lacasse
authors.forename: Michael L
authors.initials: ML
authors.lastname: Hawes
authors.forename: Carol
authors.initials: C
authors.lastname: Nelson
authors.forename: Susan
authors.initials: S
authors.lastname: Richards
authors.forename: Peter A
authors.initials: PA
authors.lastname: Piepenhagen
authors.forename: Richard D
authors.initials: RD
authors.lastname: Garman
authors.forename: Laura
authors.initials: L
authors.lastname: Andrews
authors.forename: Beth L
authors.initials: BL
authors.lastname: Thurberg
authors.forename: Scott
authors.initials: S
authors.lastname: Lonning
authors.forename: Steve
authors.initials: S
authors.lastname: Ledbetter
authors.forename: Melanie C
authors.initials: MC
authors.lastname: Ruzek
mesh_terms: D000818:Animals; D015153:Blotting, Western; D004947:Esophagus / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006706:Homeostasis / Q000502:physiology*; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry; D008407:Mast Cells / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009055:Mouth / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D012463:Saliva / Q000737:chemistry / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: D016212:Transforming Growth Factor beta