title: A novel human truncated IL12rβ1-Fc fusion protein ameliorates experimental autoimmune encephalomyelitis via specific binding of p40 to inhibit Th1 and Th17 cell differentiation.
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.
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: 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: 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.
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: Dongmei
authors.initials: D
authors.lastname: Yu
authors.affiliation: State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing, 210009 China.
authors.forename: Yuheng
authors.initials: Y
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: Yucong
authors.initials: Y
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing, 210009 China.
authors.forename: Wen
authors.initials: W
authors.lastname: Lei
authors.affiliation: State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing, 210009 China.
authors.forename: Xiangdong
authors.initials: X
authors.lastname: Gao
authors.affiliation: State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing, 210009 China.
authors.forename: Wenbing
authors.initials: W
authors.lastname: Yao
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology*; D016466:CHO Cells; D002454:Cell Differentiation / Q000187:drug effects*; D003412:Cricetulus; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D005260:Female; D006801:Humans; D018836:Inflammation Mediators / Q000276:immunology / Q000378:metabolism; D053762:Interleukin-12 Subunit p40 / Q000276:immunology / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D063308:Myelin-Oligodendrocyte Glycoprotein; D016328:NF-kappa B / Q000276:immunology / Q000378:metabolism; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000276:immunology / Q000378:metabolism; D010446:Peptide Fragments; D010641:Phenotype; D011485:Protein Binding; D011961:Receptors, Fc / Q000276:immunology / Q000378:metabolism; D053707:Receptors, Interleukin-12 / Q000276:immunology / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D050791:STAT Transcription Factors / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D020825:T-Box Domain Proteins / Q000276:immunology / Q000378:metabolism; D018417:Th1 Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D058504:Th17 Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D000098815:T-bet Transcription Factor
chemical_list: D000893:Anti-Inflammatory Agents; D016207:Cytokines; C508438:IL12RB1 protein, human; D018836:Inflammation Mediators; D053762:Interleukin-12 Subunit p40; D063308:Myelin-Oligodendrocyte Glycoprotein; D016328:NF-kappa B; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D010446:Peptide Fragments; D011961:Receptors, Fc; D053707:Receptors, Interleukin-12; D011993:Recombinant Fusion Proteins; D050791:STAT Transcription Factors; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; C445081:myelin oligodendrocyte glycoprotein (35-55)
keywords: Immune response; Immunity; Immunology and Microbiology Section; autoimmune disease; binding specificity; central nervous system; cytokine-blocking; molecular mechanism