Grape seed proanthocyanidin extract ameliorates murine autoimmune arthritis through regulation of TLR4/MyD88/NF-κB signaling pathway.
Grape seed proanthocyanidin extract (GSPE) has been reported to have a beneficial effect on regulating inf lammation. However, the anti-inflammatory mechanism of GSPE remains unclear. The aim of this study was to verify the influence of GSPE on the Toll-like receptor 4 (TLR4)-mediated signaling pathway in the regulation of murine autoimmune arthritis.



Collagen-induced arthritis (CIA) was induced in dilute brown non-agouti (DBA)/1J mice. The mice were treated with GSPE (0 or 100 mg/kg) intraperitoneally. The severity of arthritis was assessed clinically, biochemically, and histologically. Immunostaining for TLR4 was performed. The expressions of TLR4 and downstream signaling molecules were analyzed by Western blot. The effect of GSPE on lipopolysaccharide (LPS)-induced TLR4 activation was also evaluated using RAW264.7 cells and fibroblast-like synoviocytes (FLSs) from patients with rheumatoid arthritis and from those with osteoarthritis.



GSPE attenuated the clinical severity of arthritis and decreased histological damage. GSPE treatment reduced the number of TLR4-stained cells in the synovium of mice with CIA. GSPE also downregulated the expression of TLR4, myeloid differentiation factor 88 (MyD88) and phosphorylated IκBα synovial protein in CIA mice. Concurrently, GSPE inhibited the nuclear translocation of nuclear factor-κB (NF-κB) subunits (p65 and p50). LPS-induced TLR4 activation was suppressed by GSPE in human FLS as well as in murine macrophagesin vitro.



Our results demonstrated that GSPE ameliorated CIA by regulating the TLR4-MyD88-NF-κB signaling pathway.
Division of Rheumatology, Department of Internal Medicine, Keimyung University Dongsan Medical Center, Daegu, Korea.
Sang-Hyon
SH
Kim
Keimyung University School of Medicine, Daegu, Korea.
Jihye
J
Bang
Division of Rheumatology, Department of Internal Medicine, Keimyung University Dongsan Medical Center, Daegu, Korea.
Chang-Nam
CN
Son
Department of Microbiology, Keimyung University School of Medicine, Daegu, Korea.
Won-Ki
WK
Baek
Division of Rheumatology, Department of Internal Medicine, Keimyung University Dongsan Medical Center, Daegu, Korea.
Ji-Min
JM
Kim
D000818:Animals; D001168:Arthritis / Q000188:drug therapy / Q000378:metabolism; D001327:Autoimmune Diseases / Q000188:drug therapy / Q000378:metabolism; D016207:Cytokines; D056604:Grape Seed Extract / Q000494:pharmacology; D051379:Mice; D053594:Myeloid Differentiation Factor 88 / Q000187:drug effects / Q000378:metabolism; D016328:NF-kappa B / Q000187:drug effects / Q000378:metabolism; D044945:Proanthocyanidins / Q000494:pharmacology; D050794:STAT1 Transcription Factor / Q000187:drug effects; D051197:Toll-Like Receptor 4 / Q000187:drug effects / Q000378:metabolism
D016207:Cytokines; D056604:Grape Seed Extract; C511402:Grape Seed Proanthocyanidins; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D044945:Proanthocyanidins; D050794:STAT1 Transcription Factor; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4
Arthritis, experimental; Arthritis, rheumatoid; Grape seed proanthocyanidin extract; Toll-like receptor 4