title: Treatment of experimental (Trinitrobenzene sulfonic acid) colitis by intranasal administration of transforming growth factor (TGF)-beta1 plasmid: TGF-beta1-mediated suppression of T helper cell type 1 response occurs by interleukin (IL)-10 induction and IL-12 receptor beta2 chain downregulation.
abstract: In this study, we show that a single intranasal dose of a plasmid encoding active transforming growth factor beta1 (pCMV-TGF-beta1) prevents the development of T helper cell type 1 (Th1)-mediated experimental colitis induced by the haptenating reagent, 2,4, 6-trinitrobenzene sulfonic acid (TNBS). In addition, such plasmid administration abrogates TNBS colitis after it has been established, whereas, in contrast, intraperitoneal administration of rTGF-beta1 protein does not have this effect. Intranasal pCMV-TGF-beta1 administration leads to the expression of TGF-beta1 mRNA in the intestinal lamina propria and spleen for 2 wk, as well as the appearance of TGF-beta1-producing T cells and macrophages in these tissues, and is not associated with the appearances of fibrosis. These cells cause marked suppression of interleukin (IL)-12 and interferon (IFN)-gamma production and enhancement of IL-10 production; in addition, they inhibit IL-12 receptor beta2 (IL-12Rbeta2) chain expression. Coadministration of anti-IL-10 at the time of pCMV-TGF-beta1 administration prevents the enhancement of IL-10 production and reverses the suppression of IL-12 but not IFN-gamma secretion. However, anti-IL-10 leads to increased tumor necrosis factor alpha production, especially in established colitis. Taken together, these studies show that TGF-beta1 inhibition of a Th1-mediated colitis is due to: (a) suppression of IL-12 secretion by IL-10 induction and (b) inhibition of IL-12 signaling via downregulation of IL-12Rbeta2 chain expression. In addition, TGF-beta1 may also have an inhibitory effect on IFN-gamma transcription.
authors.affiliation: Mucosal Immunity Section, Laboratory of Clinical Investigation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: A
authors.initials: A
authors.lastname: Kitani
authors.forename: I J
authors.initials: IJ
authors.lastname: Fuss
authors.forename: K
authors.initials: K
authors.lastname: Nakamura
authors.forename: O M
authors.initials: OM
authors.lastname: Schwartz
authors.forename: T
authors.initials: T
authors.lastname: Usui
authors.forename: W
authors.initials: W
authors.lastname: Strober
mesh_terms: D000281:Administration, Intranasal; D000818:Animals; D003092:Colitis / Q000139:chemically induced / Q000276:immunology / Q000517:prevention & control / Q000628:therapy*; D003106:Colon / Q000473:pathology; D016207:Cytokines / Q000096:biosynthesis; D003587:Cytomegalovirus; D015316:Genetic Therapy; D007274:Injections, Intraperitoneal; D007413:Intestinal Mucosa / Q000473:pathology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D010957:Plasmids / Q000008:administration & dosage*; D011994:Recombinant Proteins / Q000627:therapeutic use; D013552:Swine; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000235:genetics* / Q000627:therapeutic use; D014302:Trinitrobenzenesulfonic Acid
chemical_list: D016207:Cytokines; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta; D014302:Trinitrobenzenesulfonic Acid