title: Stephanthraniline A suppressed CD4(+) T cell-mediated immunological hepatitis through impairing PKCθ function.
abstract: Stephanthraniline A (STA), a C21 steroid isolated from Stephanotis mucronata (Blanco) Merr., was previously shown to inhibit T cells activation and proliferation in vitro and in vivo. The purpose of this study was to further evaluate the in vivo immunosuppressive activity of STA and to elucidate its potential mechanisms. The results showed that pretreatment with STA significantly attenuated concanavalin A (Con A)-induced hepatitis and reduced CD4(+) T cells activation and aggregation in hepatic tissue in mice. STA directly suppressed the activation and proliferation of Con A-induced CD4(+) T cells, and inhibited NFAT, NFκB and MAPK signaling cascades in activated CD4(+) T cells in vitro. Moreover, it was proved that STA inhibited T cells activation and proliferation through proximal T cell-receptor (TCR) signaling- and Ca(2+) signaling-independent way. The molecular docking studies predicted that STA could tight bind to PKCθ via five hydrogen. The further findings indicated STA directly inhibited PKCθ kinase activity, and its phosphorylation in activated CD4(+) T cells in vitro. Collectively, the present study indicated that STA could protect against CD4(+) T cell-mediated immunological hepatitis in mice through PKCθ and its downstream NFAT, NFκB and MAPK signaling cascades. These results highlight the potential of STA as an effective leading compound for use in the treatment of CD4(+) T cell-mediated inflammatory and autoimmune diseases.
authors.affiliation: Key Laboratory of Animal Virology of Ministry of Agriculture, College of Animal Sciences, Zhejiang University, Hangzhou 310058, China; Institute of Materia Medica, Zhejiang Academy of Medical Sciences, Hangzhou 310013, China.
authors.forename: Feng-Yang
authors.initials: FY
authors.lastname: Chen
authors.affiliation: Zhejiang Cancer Hospital, Hangzhou 310022, China.
authors.forename: Li-Fei
authors.initials: LF
authors.lastname: Zhou
authors.affiliation: Institute of Materia Medica, Zhejiang Academy of Medical Sciences, Hangzhou 310013, China.
authors.forename: Xiao-Yu
authors.initials: XY
authors.lastname: Li
authors.affiliation: Institute of Materia Medica, Zhejiang Academy of Medical Sciences, Hangzhou 310013, China.
authors.forename: Jia-Wen
authors.initials: JW
authors.lastname: Zhao
authors.affiliation: Institute of Materia Medica, Zhejiang Academy of Medical Sciences, Hangzhou 310013, China.
authors.forename: Shi-Fang
authors.initials: SF
authors.lastname: Xu
authors.affiliation: Institute of Materia Medica, Zhejiang Academy of Medical Sciences, Hangzhou 310013, China.
authors.forename: Wen-Hai
authors.initials: WH
authors.lastname: Huang
authors.affiliation: Institute of Materia Medica, Zhejiang Academy of Medical Sciences, Hangzhou 310013, China.
authors.forename: Li-Juan
authors.initials: LJ
authors.lastname: Gao
authors.affiliation: Institute of Materia Medica, Zhejiang Academy of Medical Sciences, Hangzhou 310013, China.
authors.forename: Shu-Juan
authors.initials: SJ
authors.lastname: Hao
authors.affiliation: Institute of Materia Medica, Zhejiang Academy of Medical Sciences, Hangzhou 310013, China. Electronic address: yeyiping2005@163.com.
authors.forename: Yi-Ping
authors.initials: YP
authors.lastname: Ye
authors.affiliation: Key Laboratory of Animal Virology of Ministry of Agriculture, College of Animal Sciences, Zhejiang University, Hangzhou 310058, China. Electronic address: sunhx@zju.edu.cn.
authors.forename: Hong-Xiang
authors.initials: HX
authors.lastname: Sun
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology*; D020013:Calcium Signaling / Q000187:drug effects; D020134:Catalytic Domain; D002449:Cell Aggregation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004224:Diterpenes / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D006505:Hepatitis / Q000188:drug therapy* / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D007527:Isoenzymes / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D062105:Molecular Docking Simulation; D016328:NF-kappa B / Q000378:metabolism; D050778:NFATC Transcription Factors / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011493:Protein Kinase C / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D000074121:Protein Kinase C-theta; D011494:Protein Kinases / Q000378:metabolism
chemical_list: D004224:Diterpenes; D007527:Isoenzymes; D016328:NF-kappa B; D050778:NFATC Transcription Factors; C555640:stephanthraniline A; D011494:Protein Kinases; C403405:Smok1 protein, mouse; C489593:Prkcq protein, mouse; D011493:Protein Kinase C; D000074121:Protein Kinase C-theta
keywords: C(21) steroid; CD4(+) T cells; Cyclosporine A (PubChem CID: 5284373); Immunosuppressant; PKCθ; Stephanthraniline A; Stephanthraniline A (PubChem CID: 102482096)