title: The immunobiology of colitis and cholangitis in interleukin-23p19 and interleukin-17A deleted dominant negative form of transforming growth factor beta receptor type II mice.
abstract: Dominant negative form of transforming growth factor beta receptor type II (dnTGFβRII) mice, expressing a dominant negative form of TGFβ receptor II under control of the CD4 promoter, develop autoimmune colitis and cholangitis. Deficiency in interleukin (IL)-12p40 lead to a marked diminution of inflammation in both the colon and the liver. To distinguish whether IL-12p40 mediates protection by the IL-12 or IL-23 pathways, we generated an IL-23p19(-/-) dnTGFβRII strain deficient in IL-23, but not in IL-12; mice were longitudinally followed for changes in the natural history of disease and immune responses. Interestingly, IL-23p19(-/-) mice demonstrate dramatic improvement in their colitis, but no changes in biliary pathology; mice also manifest reduced T-helper (Th)17 cell populations and unchanged IFN-γ levels. We submit that the IL-12/Th1 pathway is essential for biliary disease pathogenesis, whereas the IL-23/Th17 pathway mediates colitis. To further assess the mechanism of the IL-23-mediated protection from colitis, we generated an IL-17A(-/-) dnTGFβRII strain deficient in IL-17, a major effector cytokine produced by IL-23-dependent Th17 cells. Deletion of the IL-17A gene did not affect the severity of either cholangitis or colitis, suggesting that the IL-23/Th17 pathway contributes to colon disease in an IL-17-independent manner. These results affirm that the IL-12/Th1 pathway is critical to biliary pathology in dnTGFβRII mice, whereas colitis is caused by a direct effect of IL-23.
authors.affiliation: Division of Rheumatology, Allergy, and Clinical Immunology, University of California at Davis, Davis, CA 95616, USA.
authors.forename: Yugo
authors.initials: Y
authors.lastname: Ando
authors.forename: Guo-Xiang
authors.initials: GX
authors.lastname: Yang
authors.forename: Masanobu
authors.initials: M
authors.lastname: Tsuda
authors.forename: Kazuhito
authors.initials: K
authors.lastname: Kawata
authors.forename: Weici
authors.initials: W
authors.lastname: Zhang
authors.forename: Takahiko
authors.initials: T
authors.lastname: Nakajima
authors.forename: Koichi
authors.initials: K
authors.lastname: Tsuneyama
authors.forename: Patrick
authors.initials: P
authors.lastname: Leung
authors.forename: Zhe-Xiong
authors.initials: ZX
authors.lastname: Lian
authors.forename: Kazuichi
authors.initials: K
authors.lastname: Okazaki
authors.forename: William M
authors.initials: WM
authors.lastname: Ridgway
authors.forename: Gary L
authors.initials: GL
authors.lastname: Norman
authors.forename: Aftab A
authors.initials: AA
authors.lastname: Ansari
authors.forename: Xiao-Song
authors.initials: XS
authors.lastname: He
authors.forename: Ross L
authors.initials: RL
authors.lastname: Coppel
authors.forename: M Eric
authors.initials: ME
authors.lastname: Gershwin
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D015415:Biomarkers / Q000097:blood; D001707:Biopsy, Needle; D002761:Cholangitis / Q000235:genetics / Q000276:immunology* / Q000503:physiopathology; D003092:Colitis / Q000235:genetics / Q000276:immunology* / Q000503:physiopathology; D016207:Cytokines / Q000032:analysis / Q000097:blood; D004195:Disease Models, Animal; D018450:Disease Progression; D005434:Flow Cytometry; D017353:Gene Deletion; D007150:Immunohistochemistry; D020381:Interleukin-17 / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D053760:Interleukin-23 Subunit p19 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008817:Mice, Mutant Strains; D016133:Polymerase Chain Reaction / Q000379:methods; D011897:Random Allocation; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D012680:Sensitivity and Specificity; D018709:Statistics, Nonparametric
chemical_list: D015415:Biomarkers; D016207:Cytokines; D020381:Interleukin-17; D053760:Interleukin-23 Subunit p19; D018125:Receptors, Transforming Growth Factor beta