Apigenin, a non-mutagenic dietary flavonoid, suppresses lupus by inhibiting autoantigen presentation for expansion of autoreactive Th1 and Th17 cells
| Autor: | Hee Kap Kang, Diane Ecklund, Michael Liu, Syamal K. Datta |
|---|---|
| Jazyk: | angličtina |
| Předmět: |
Antigen presentation
Immunology Lupus nephritis Antigen-Presenting Cells Apoptosis Enzyme-Linked Immunosorbent Assay Biology Lymphocyte Activation Autoantigens 03 medical and health sciences chemistry.chemical_compound Interferon-gamma Mice 0302 clinical medicine Immune system Antigen Rheumatology T-Lymphocyte Subsets medicine Cytotoxic T cell Animals Lupus Erythematosus Systemic Immunology and Allergy Apigenin Antigen-presenting cell 030304 developmental biology Autoantibodies 0303 health sciences Antigen Presentation B-Lymphocytes Systemic lupus erythematosus Mice Inbred NZB Interleukin-17 Th1 Cells medicine.disease Flow Cytometry Lupus Nephritis 3. Good health Nucleosomes chemistry Cyclooxygenase 2 Immunoglobulin G Cancer research 030215 immunology Research Article |
| Zdroj: | Arthritis Research & Therapy |
| ISSN: | 1478-6354 |
| DOI: | 10.1186/ar2682 |
| Popis: | Introduction 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-κB)-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 μM, compared with concentrations (10 to 100 μM) 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-κB-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-κB 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). |
| Databáze: | OpenAIRE |
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