Apigenin, a non-mutagenic dietary flavonoid, suppresses lupus by inhibiting autoantigen presentation for expansion of autoreactive Th1 and Th17 cells.
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).
Kang
Hee-Kap
HK
Department of Medicine and Microbiology-Immunology, Division of Rheumatology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA. hkk465@northwestern.edu
Ecklund
Diane
D
Liu
Michael
M
Datta
Syamal K
SK
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
D001323:Autoantibodies; D001324:Autoantigens; D007074:Immunoglobulin G; D020381:Interleukin-17; D009707:Nucleosomes; D047310:Apigenin; D007371:Interferon-gamma; D051546:Cyclooxygenase 2