Oncotarget

Research Papers: Immunology:

A novel human truncated IL12rβ1-Fc fusion protein ameliorates experimental autoimmune encephalomyelitis via specific binding of p40 to inhibit Th1 and Th17 cell differentiation

Wei Guo, Chen Wang, Xin Wang, Cheng Luo, Dongmei Yu, Yuheng Wang, Yucong Chen, Wen Lei, Xiangdong Gao _ and Wenbing Yao

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Oncotarget. 2015; 6:28539-28555. https://doi.org/10.18632/oncotarget.5164

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Abstract

Wei Guo1,*, Chen Wang1,*, Xin Wang1, Cheng Luo1, Dongmei Yu1, Yuheng Wang1, Yucong Chen1, Wen Lei1, Xiangdong Gao1, Wenbing Yao1

1State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing, 210009 China

*These authors have contributed equally to this work

Correspondence to:

Xiangdong Gao, e-mail: xdgao@cpu.edu.cn

Wenbing Yao, e-mail: wbyao@cpu.edu.cn

Keywords: Immunology and Microbiology Section, Immune response, Immunity, cytokine-blocking, binding specificity, molecular mechanism, central nervous system, autoimmune disease

Received: May 24, 2015     Accepted: August 22, 2015     Published: September 04, 2015

ABSTRACT

Interleukin (IL)-12 and IL-23 respectively driving polarization of T helper (Th) 1 and Th17 cells has been strongly implicated in the pathogenesis of both multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE). In this study, we first constructed, expressed and purified a novel human truncated IL12rβ1-Fc fusion protein (tIL12rβ1/Fc) binding multiple forms of the p40 subunit of human IL-12 and IL-23. tIL12rβ1/Fc was found to effectively ameliorate MOG35–55-induced EAE through reducing the production of Th1- and Th17-polarized pro-inflammatory cytokines and suppressing inflammation and demyelination in the focused parts. Moreover, tIL12rβ1/Fc suppressed Th1 (IFN-γ+ alone) and IFN-γ+ IL-17+ as well as the population of classic Th17 (IL-17+ alone) cells in vivo. Furthermore, tIL12rβ1/Fc ameliorated EAE at the peak of disease via the inhibition of STAT pathway, thereby causing a prominent reduction of RORγt (Th17) and T-bet (Th1) expression. Notably, tIL12rβ1/Fc could increase the relative number of CD4+ Foxp3+ regulatory T cells. These findings indicates that tIL12rβ1/Fc is a novel fusion protein for specific binding multiple forms of p40 subunit to exert potent anti-inflammatory effects and provides a valuable approach for the treatment of MS and other autoimmune diseases.


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