title: Suppression of human and mouse Th17 differentiation and autoimmunity by an endogenous Interleukin 23 receptor cytokine-binding homology region.
abstract: T-helper 17 (Th17) cells, a recently identified CD4+ T subset with a unique characteristic to produce Interleukin-17 (IL-17), are critical for the development of autoimmune diseases such as multiple sclerosis, in which IL-23 plays an important role in the differentiation of Th17 cells through IL-23/IL-23-receptor/STAT3 pathway. Previously, soluble recombinant human IL-23 receptor cytokine-binding homology region (hIL23R-CHR) was constructed in our laboratory to neutralize IL-23 and inhibit murine Th17 development in vitro. Herein we present that hIL23R-CHR could inhibit both differentiation and function of human/murine Th17 cells. The present in vivo study further demonstrated that hIL23R-CHR inhibited murine Th17 cell development by down regulating IL-17 gene expression and protected mice against the development of experimental autoimmune encephalomyelitis (EAE) through suppression of CNS inflammation and pro-inflammatory cytokine production. In addition to the in vitro inhibition of human Th17 cells in a dose-dependent manner, the antagonizing effect of hIL23R-CHR was confirmed by reduced levels of IL-23 in both blood and brain of EAE mice and STAT3 phosphorylation in vivo. Taken together, our data demonstrated that hIL23R-CHR could be an effective and specific immunosuppressive molecule for the treatment of Th17-related autoimmune diseases.
authors.affiliation: State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Guo
authors.affiliation: State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Luo
authors.affiliation: State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Chen
authors.initials: C
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Yu Heng
authors.initials: YH
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, China. Electronic address: xdgao@cpu.edu.cn.
authors.forename: Xiang Dong
authors.initials: XD
authors.lastname: Gao
authors.affiliation: State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, China. Electronic address: wbyao@cpu.edu.cn.
authors.forename: Wen Bing
authors.initials: WB
authors.lastname: Yao
mesh_terms: D000818:Animals; D015551:Autoimmunity / Q000187:drug effects* / Q000235:genetics / Q000276:immunology; D002454:Cell Differentiation / Q000187:drug effects* / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology / Q000517:prevention & control; D005260:Female; D005434:Flow Cytometry; D015870:Gene Expression / Q000187:drug effects / Q000276:immunology; D006801:Humans; D020381:Interleukin-17 / Q000276:immunology / Q000378:metabolism; D053759:Interleukin-23 / Q000097:blood / Q000276:immunology / Q000378:metabolism; D008810:Mice, Inbred C57BL; D010446:Peptide Fragments / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D018123:Receptors, Interleukin / Q000737:chemistry / Q000235:genetics; D011994:Recombinant Proteins / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000276:immunology / Q000378:metabolism; D058504:Th17 Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism
chemical_list: D016207:Cytokines; C515500:IL23R protein, human; D020381:Interleukin-17; D053759:Interleukin-23; D010446:Peptide Fragments; D018123:Receptors, Interleukin; D011994:Recombinant Proteins; D050796:STAT3 Transcription Factor
keywords: Experimental autoimmune encephalomyelitis; IL-23; IL-23R; Multiple sclerosis; Th17