TY - JOUR T1 - Targeting tumour necrosis factor receptor 1 assembly reverses Th17-mediated colitis through boosting a Th2 response JF - Gut JO - Gut SP - 765 LP - 775 DO - 10.1136/gutjnl-2013-306585 VL - 64 IS - 5 AU - Shin-Huei Fu AU - Ming-Hong Lin AU - Li-Tzu Yeh AU - Yen-Ling Wang AU - Ming-Wei Chien AU - Shih-Hua Lin AU - Deh-Ming Chang AU - Huey-Kang Sytwu Y1 - 2015/05/01 UR - http://gut.bmj.com/content/64/5/765.abstract N2 - Objective The soluble preligand assembly domain (PLAD) of tumour necrosis factor receptor 1 (TNFR1) interferes with receptor trimerisation to block downstream signalling, and mediates Th17 suppression. We explored the therapeutic potential of recombinant PLAD.Fc protein on a spontaneous experimental colitis. Design A T-cell-specific BLIMP-1 knockout mouse model with mixed Th1/Th17 responses, resembling human Crohn's disease (CD) was established, and its colitogenic phenotype was characterised. Mice, 9 weeks old, were treated with PLAD.Fc protein at 5 mg/kg of body weight twice per week for 16 weeks, and presence of colitis was monitored by the appearance of diarrhoea, weight loss, and by histological colonic scoring. Activation status, cytokine profiles, and transcription factors in T cells were further analysed. Results The colitogenic phenotype in BLIMP-1 knockout mice was alleviated when an interleukin (IL)-23 knockdown transgene was introduced, indicating a therapeutic potential by downregulating IL-23-Th17 axis in these knockout mice. In PLAD.Fc-treated group, the mouse body weight remained stable and only mild disease scores were revealed. The percentage of naive CD4 T cells was increased and that of effector/memory CD4 T cells was decreased after PLAD.Fc-treatment. Moreover, the levels of IFN-γ, IL-17, IL-21, IL-22, IL-23R, granulocyte-macrophage colony-stimulating factor (GM-CSF) and TNF-α were diminished. Strikingly, Th2-associated cytokines (IL-4, IL-13 and IL-10) in sera, as well as percentages of Th2 cells, were increased in PLAD.Fc-treated mice. However, PLAD.Fc-mediated suppression of effector phenotypes in Th1/Th17 was abrogated after neutralising IL-10. Conclusions The Th2 cytokine milieu induced by PLAD.Fc rebalanced T-helper cell subsets and conferred a protection against colitis in BLIMP-1 knockout mice. ER -