title: T cell-mediated pathology in two models of experimental colitis depends predominantly on the interleukin 12/Signal transducer and activator of transcription (Stat)-4 pathway, but is not conditional on interferon gamma expression by T cells.
abstract: The requirements for interleukin (IL)-12/signal transducer and activator of transcription (Stat)-4 signaling and induction of T cell-specific interferon (IFN)-gamma expression in the development of T helper cell (Th)1-type pathology were examined in two different models of experimental colitis. In each model, abnormal reconstitution of the T cell compartment in immunodeficient mice by adoptive cell transfer leads to a wasting syndrome and inflammation of the colon, induced by IFN-gamma and tumor necrosis factor (TNF)-alpha-producing T cells. We show here that treatment with anti-IL-12 antibodies in one of the models, or reconstitution with T cells from Stat-4-deficient (Stat-4(null)) mice in both models resulted in a milder disease in the majority of recipient animals, compared with those that were left untreated or that had been reconstituted with wt cells. Protected mice in each group also harbored lower frequencies of IFN-gamma-producing T cells than did diseased mice, suggesting that effects on wasting and colitis resulted from the attenuation of IFN-gamma expression by T cells. To test whether the development of pathogenic T cells in the two colitis models was directly dependent on T cell-specific IFN-gamma expression, IFN-gammanull donors were used for T cell reconstitution in each system. Surprisingly, large numbers of IFN-gammanull-reconstituted mice developed wasting and colitis, which in many cases was of comparable severity to that seen in animals reconstituted with wt cells. Furthermore, T cells from these animals expressed TNF-alpha, demonstrating that they had retained the ability to produce another proinflammatory cytokine. Taken together, these results demonstrate that in some forms of chronic experimental colitis the development of pathogenic T cells is influenced predominantly, though not exclusively, by IL-12 via the actions of Stat-4 proteins. Furthermore, our data suggest that in the models of colitis studied here the effects of IL-12/Stat-4 or other Th1 promoting pathways are not limited to the induction of IFN-gamma gene expression in T lymphocytes.
authors.affiliation: Division of Immunology, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02115, USA.
authors.forename: S J
authors.initials: SJ
authors.lastname: Simpson
authors.forename: S
authors.initials: S
authors.lastname: Shah
authors.forename: M
authors.initials: M
authors.lastname: Comiskey
authors.forename: Y P
authors.initials: YP
authors.lastname: de Jong
authors.forename: B
authors.initials: B
authors.lastname: Wang
authors.forename: E
authors.initials: E
authors.lastname: Mizoguchi
authors.forename: A K
authors.initials: AK
authors.lastname: Bhan
authors.forename: C
authors.initials: C
authors.lastname: Terhorst
mesh_terms: D000818:Animals; D003092:Colitis / Q000209:etiology* / Q000276:immunology / Q000473:pathology / Q000628:therapy; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D016219:Immunotherapy, Adoptive; D007371:Interferon-gamma / Q000096:biosynthesis*; D018664:Interleukin-12 / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008817:Mice, Mutant Strains; D050797:STAT4 Transcription Factor; D015398:Signal Transduction; D018417:Th1 Cells / Q000276:immunology*; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D019282:Wasting Syndrome
chemical_list: D004268:DNA-Binding Proteins; D050797:STAT4 Transcription Factor; C494091:Stat4 protein, mouse; D015534:Trans-Activators; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12; D007371:Interferon-gamma