title: Oral administration of recombinant cholera toxin subunit B inhibits IL-12-mediated murine experimental (trinitrobenzene sulfonic acid) colitis.
abstract: Trinitrobenzene sulfonic acid (TNBS)-induced colitis is an IL-12-driven, Th1 T cell-mediated colitis that resembles human Crohn's disease. In the present study, we showed initially that the oral administration of recombinant subunit B of cholera toxin (rCT-B) at the time of TNBS-induced colitis by intrarectal TNBS instillation inhibits the development of colitis or, at later time when TNBS-induced colitis is well established, brings about resolution of the colitis. Dose-response studies showed that a majority of mice (68%) treated with rCT-B at a dose of 100 microg (times four daily doses) exhibited complete inhibition of the development of colitis, whereas a minority (30%) treated with rCT-B at a dose of 10 microg (times four daily doses) exhibited complete inhibition; in both cases, however, the remaining mice exhibited some reduction in the severity of inflammation. In further studies, we showed that rCT-B administration is accompanied by prevention/reversal of increased IFN-gamma secretion (the hallmark of a Th1 response) without at the same time causing an increase in IL-4 secretion. This decreased IFN-gamma secretion was not associated with the up-regulation of the secretion of counterregulatory cytokines (IL-10 or TGF-beta), but was associated with a marked inhibition of IL-12 secretion, i.e., the secretion of the cytokine driving the Th1 response. Finally, we showed that rCT-B administration results in increased apoptosis of lamina propria cells, an effect previously shown to be indicative of IL-12 deprivation. From these studies, rCT-B emerges as a powerful inhibitor of Th1 T cell-driven inflammation that can conceivably be applied to the treatment of Crohn's disease.
authors.affiliation: Laboratory of Immunology, Istituto Superiore di Sanità, Rome, Italy. monboir@iss.it
authors.forename: M
authors.initials: M
authors.lastname: Boirivant
authors.forename: I J
authors.initials: IJ
authors.lastname: Fuss
authors.forename: L
authors.initials: L
authors.lastname: Ferroni
authors.forename: M
authors.initials: M
authors.lastname: De Pascale
authors.forename: W
authors.initials: W
authors.lastname: Strober
mesh_terms: D000284:Administration, Oral; D000285:Administration, Rectal; D000818:Animals; D017209:Apoptosis / Q000276:immunology; D002478:Cells, Cultured; D002772:Cholera Toxin / Q000008:administration & dosage* / Q000276:immunology*; D003092:Colitis / Q000139:chemically induced / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control*; D003106:Colon / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D018450:Disease Progression; D007371:Interferon-gamma / Q000096:biosynthesis; D016753:Interleukin-10 / Q000096:biosynthesis; D018664:Interleukin-12 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000502:physiology*; D015847:Interleukin-4 / Q000096:biosynthesis; D007413:Intestinal Mucosa / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D010081:Oxazolone / Q000008:administration & dosage; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000096:biosynthesis; D014302:Trinitrobenzenesulfonic Acid / Q000008:administration & dosage / Q000037:antagonists & inhibitors
chemical_list: D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta; D016753:Interleukin-10; D010081:Oxazolone; D018664:Interleukin-12; D015847:Interleukin-4; D007371:Interferon-gamma; D014302:Trinitrobenzenesulfonic Acid; D002772:Cholera Toxin