title: Cutting edge: chronic intestinal inflammation in STAT-4 transgenic mice: characterization of disease and adoptive transfer by TNF- plus IFN-gamma-producing CD4+ T cells that respond to bacterial antigens.
abstract: We generated transgenic mice for STAT-4, a regulatory protein specifically associated with IL-12 signaling, under the control of a CMV promoter. These mice expressed strikingly increased nuclear STAT-4 levels in lamina propria CD4+ T lymphocytes upon systemic administration of dinitrophenyl-keyhole limpet hemocyanin and developed chronic transmural colitis characterized by infiltrates of mainly CD4+ T lymphocytes. The latter cells produced predominantly TNF and IFN-gamma but not IL-4 upon activation with alphaCD3/CD28 or autologous bacterial Ags, consistent with a Th1-type cell response. Furthermore, chronic colitis in STAT-4 transgenic mice could be adoptively transferred to SCID mice by colonic and splenic CD4+ T cells that were activated with Ags from autologous bacterial flora. These data establish a critical molecular signaling pathway involving STAT-4 for the pathogenesis of chronic intestinal inflammation, and targeting of this pathway may be relevant for the treatment of colitis in humans.
authors.affiliation: Laboratory of Immunology, I. Medical Clinic, University of Mainz, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Wirtz
authors.forename: S
authors.initials: S
authors.lastname: Finotto
authors.forename: S
authors.initials: S
authors.lastname: Kanzler
authors.forename: A W
authors.initials: AW
authors.lastname: Lohse
authors.forename: M
authors.initials: M
authors.lastname: Blessing
authors.forename: H A
authors.initials: HA
authors.lastname: Lehr
authors.forename: P R
authors.initials: PR
authors.lastname: Galle
authors.forename: M F
authors.initials: MF
authors.lastname: Neurath
mesh_terms: D019264:Adoptive Transfer / Q000379:methods; D000818:Animals; D000942:Antigens, Bacterial / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D002908:Chronic Disease; D003092:Colitis / Q000235:genetics / Q000276:immunology* / Q000382:microbiology / Q000473:pathology*; D003433:Crosses, Genetic; D016207:Cytokines / Q000096:biosynthesis; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics*; D006241:Haptens / Q000276:immunology; D006433:Hemocyanins / Q000276:immunology; D007371:Interferon-gamma / Q000096:biosynthesis*; D007413:Intestinal Mucosa / Q000378:metabolism / Q000382:microbiology; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008815:Mice, Inbred Strains; D016513:Mice, SCID; D008822:Mice, Transgenic; D050797:STAT4 Transcription Factor; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D015534:Trans-Activators / Q000096:biosynthesis / Q000235:genetics*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*