RESEARCH - Apigenin, a non-mutagenic dietary flavonoid, suppresses lupus by inhibiting autoantigen presentation for expansion of autoreactive Th1 and Th17 cells

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Arthritis Research & Therapy 2009, 11:R59doi:10.1186/ar2682

Published: 30 April 2009

Research article

Apigenin, a non-mutagenic dietary flavonoid, suppresses lupus by

inhibiting autoantigen presentation for expansion of autoreactive Th1

and Th17 cells

Hee-Kap Kang , Diane Ecklund , Liu and Syamal K Datta

Abstract (provisional)

Introduction

Lupus patients need alternatives to steroids and cytotoxic drugs. We

recently found that apigenin, a nonmutagenic dietary flavonoid, can

sensitize recurrently activated, normal human T cells to apoptosis by

inhibiting NFkB-regulated BclXL, 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 contributes

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

20mg/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 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

and nucleosome stimulation 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 without causing generalized

immunosuppression. Apigenin downregulated COX-2 expression in active

lupus T cells, B cells and antigen-presenting cells (APCs), and caused

their apoptosis. Autoantigen presentation and Th17-inducing cytokine

production by dendritic cells (DCs) were more sensitive to the

inhibitory effect of apigenin in culture, as evident at 0.3-3 microM,

compared to concentrations (10-100 microM) required for inducing

apoptosis.

Conclusions

Apigenin inhibits autoantigen-presenting and stimulatory functions of

APCs necessary for activation and expansion of autoreactive Th1 and

Th17 cells and B cells in lupus. Apigenin also causes apoptosis of

hyperactive lupus APCs, T and B cells, probably by inhibiting

expression of NFkB regulated anti-apoptotic molecules, especially

COX-2 and c-FLIP, which are persistently hyper-expressed by lupus

immune cells. Increasing the bioavailability of dietary plant-derived

COX-2 and NFkB inhibitors, such as apigenin, could be valuable for

suppressing inflammation in lupus and other Th17-mediated diseases

like rheumatoid arthritis, Crohn's and psoriasis, and in prevention of

inflammation-based cancers overexpressing COX-2.

http://arthritis-research.com/content/11/2/R59/abstract

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