title: Apigenin, a non-mutagenic dietary flavonoid, suppresses lupus by inhibiting autoantigen presentation for expansion of autoreactive Th1 and Th17 cells.
abstract: BACKGROUND
  Lupus patients need alternatives to steroids and cytotoxic drugs. We recently found that apigenin, a non-mutagenic dietary flavonoid, can sensitize recurrently activated, normal human T cells to apoptosis by inhibiting nuclear factor-kappa-B (NF-kappaB)-regulated Bcl-xL, cyclooxygenase 2 (COX-2), and cellular FLICE-like inhibitory protein (c-FLIP) expression. Because sustained immune activation and hyperexpression of COX-2 and c-FLIP contribute to lupus, we treated SNF1 mice that spontaneously develop human lupus-like disease with apigenin.
  
  
  METHODS
  SNF1 mice with established lupus-like disease were injected with 20 mg/kg of apigenin daily and then monitored for development of severe nephritis. Histopathologic changes in kidneys, IgG autoantibodies to nuclear autoantigens in serum and in cultures of splenocytes, along with nucleosome-specific T helper 1 (Th1) and Th17 responses, COX-2 expression, and apoptosis of lupus immune cells were analyzed after apigenin treatment.
  
  
  RESULTS
  Apigenin in culture suppressed responses of Th1 and Th17 cells to major lupus autoantigen (nucleosomes) up to 98% and 92%, respectively, and inhibited the ability of lupus B cells to produce IgG class-switched anti-nuclear autoantibodies helped by these Th cells in presence of nucleosomes by up to 82%. Apigenin therapy of SNF1 mice with established lupus suppressed serum levels of pathogenic autoantibodies to nuclear antigens up to 97% and markedly delayed development of severe glomerulonephritis. Apigenin downregulated COX-2 expression in lupus T cells, B cells, and antigen-presenting cells (APCs) and caused their apoptosis. Autoantigen presentation and Th17-inducing cytokine production by dendritic cells were more sensitive to the inhibitory effect of apigenin in culture, as evident at 0.3 to 3 muM, compared with concentrations (10 to 100 microM) required for inducing apoptosis.
  
  
  CONCLUSIONS
  Apigenin inhibits autoantigen-presenting and stimulatory functions of APCs necessary for the activation and expansion of autoreactive Th1 and Th17 cells and B cells in lupus. Apigenin also causes apoptosis of hyperactive lupus APCs and T and B cells, probably by inhibiting expression of NF-kappaB-regulated anti-apoptotic molecules, especially COX-2 and c-FLIP, which are persistently hyperexpressed by lupus immune cells. Increasing the bioavailability of dietary plant-derived COX-2 and NF-kappaB inhibitors, such as apigenin, could be valuable for suppressing inflammation in lupus and other Th17-mediated diseases like rheumatoid arthritis, Crohn disease, and psoriasis and in prevention of inflammation-based tumors overexpressing COX-2 (colon, breast).
authors.affiliation: Department of Medicine and Microbiology-Immunology, Division of Rheumatology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA. hkk465@northwestern.edu
authors.forename: Hee-Kap
authors.initials: HK
authors.lastname: Kang
authors.forename: Diane
authors.initials: D
authors.lastname: Ecklund
authors.forename: Michael
authors.initials: M
authors.lastname: Liu
authors.forename: Syamal K
authors.initials: SK
authors.lastname: Datta
mesh_terms: D000818:Animals; D017951:Antigen Presentation / Q000187:drug effects* / Q000276:immunology; D000938:Antigen-Presenting Cells / Q000187:drug effects / Q000276:immunology; D047310:Apigenin / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001323:Autoantibodies / Q000096:biosynthesis / Q000097:blood / Q000187:drug effects; D001324:Autoantigens / Q000276:immunology*; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology; D051546:Cyclooxygenase 2; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D007074:Immunoglobulin G / Q000096:biosynthesis / Q000097:blood / Q000187:drug effects; D007371:Interferon-gamma / Q000096:biosynthesis / Q000187:drug effects; D020381:Interleukin-17 / Q000276:immunology; D008180:Lupus Erythematosus, Systemic / Q000276:immunology*; D008181:Lupus Nephritis / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008814:Mice, Inbred NZB; D009707:Nucleosomes / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000187:drug effects* / Q000276:immunology; D018417:Th1 Cells / Q000187:drug effects* / Q000276:immunology
chemical_list: D001323:Autoantibodies; D001324:Autoantigens; D007074:Immunoglobulin G; D020381:Interleukin-17; D009707:Nucleosomes; D047310:Apigenin; D007371:Interferon-gamma; D051546:Cyclooxygenase 2