title: H1521, a novel derivative of 4-hydroxyquinoline-3-carboxamide, suppresses the development of lupus in mice by inducing Th1 cytokine profile in T cells.
abstract: Transferring parental splenocytes into unirradiated F1 mice induces a chronic graft-versus-host disease (GVHD), characterized by the production of Th2 cytokines and immunocomplex-mediated glomerulonephritis resembling systemic lupus erythematosus (SLE). The effects of H1521, a new derivative of 4-hydroxyquinoline-3-carboxamide, were investigated in chronic GVHD lupus model. H1521 was administered to chronic GVHD mice for 10 weeks. Nephritic symptoms were monitored and cytokine expression in the spleen was detected. To clarify the direct effect of H1521 on CD4(+) T cell, CD4(+) T cells were isolated and co-cultured with H1521 under neutral and Th1 or Th2 driving conditions in vitro. H1521 (32 mg/kg) reduced the incidence of proteinuria by 50% in chronic GVHD mice. Ameliorated lupus symptoms and improved renal histopathology damage were also observed. Administration of H1521 had little impact on Th1 cytokine IL-2 and IFN-gamma or Th2 cytokine IL-4 and IL-10 mRNA expression. In contrast, severely deficient IFN-gamma production by concanavalin A-stimulated spleen cells in chronic GVHD mice was completely restored by H1521. In accordance with this, decreased T-bet mRNA expression became normalized with H1521 (32 mg/kg) treatment. In addition, in vitro studies demonstrated that H1521 preferentially favored Th1 differentiation in CD4(+) T cell and promoted IFN-gamma secretion in Th1 differential CD4(+) T cell. However, IL-4 secretion in naive or Th2 differential CD4(+) T cell was unaffected by H1521. In conclusion, H1521 can induce Th1 cytokine profile in CD4(+) T cells and has possible therapeutic value in Th2-predominant immune diseases.
authors.affiliation: Beijing Institute of Pharmacology and Toxicology, Beijing 100850, People's Republic of China.
authors.forename: Zhi-yong
authors.initials: ZY
authors.lastname: Xiao
authors.forename: Shao-hui
authors.initials: SH
authors.lastname: Chen
authors.forename: Wen-xia
authors.initials: WX
authors.lastname: Zhou
authors.forename: Yong-xiang
authors.initials: YX
authors.lastname: Zhang
authors.forename: Jun-peng
authors.initials: JP
authors.lastname: Cheng
authors.forename: Ri-fang
authors.initials: RF
authors.lastname: Yang
mesh_terms: D000276:Adjuvants, Immunologic / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D002908:Chronic Disease; D016207:Cytokines / Q000096:biosynthesis* / Q000276:immunology; D004195:Disease Models, Animal; D005260:Female; D006086:Graft vs Host Disease / Q000188:drug therapy* / Q000276:immunology; D006912:Hydroxyquinolines / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D008180:Lupus Erythematosus, Systemic / Q000276:immunology / Q000517:prevention & control*; D051379:Mice; D008815:Mice, Inbred Strains; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology*; D018418:Th2 Cells / Q000187:drug effects / Q000276:immunology
chemical_list: C559381:((1-ethylpyrrolidin-2-yl) methyl)-4-hydroxy-7-methoxy-quinoline-3-carboxamide; D000276:Adjuvants, Immunologic; D016207:Cytokines; D006912:Hydroxyquinolines; C045282:roquinimex