Grape Seed Proanthocyanidin Extract–Mediated Regulation of STAT3 Proteins Contributes to Treg Differentiation and Attenuates Inflammation in a Murine Model of Obesity-Associated Arthritis

Joo Yeon Jhun,Jae Kyung Byun,Ji Hyeon Ju,Bo Young Yoon,Yeon Sik Hong,Jun Ki Min,Ho Youn Kim,Eun Kyung Kim,Mi-La Cho,Eun Ji Yang,Su-Jin Moon,Sung Hwan Park,Derya Unutmaz

doi:10.1371/journal.pone.0078843

Joo Yeon Jhun, Jae Kyung Byun + Show 11 more

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https://doi.org/10.1371/journal.pone.0078843

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Abstract

Grape seed proanthocyanidin extract (GSPE) is a natural flavonoid that exerts anti-inflammatory properties. Obesity is an inflammatory condition and inflammatory cells and their secretion of pro-inflammatory molecules contribute to the pathogenesis of obesity. Rheumatoid arthritis (RA) is a chronic autoimmune disease that is characterized by inflammation of joints lined by synovium. Previously, we demonstrated that obesity augmented arthritis severity in collagen induced arthritis (CIA), a murine model of human RA. Here, we investigated whether oral administration of GSPE showed antiobesity and anti-arthritic effects in high-fat diet-induced obese (DIO) mice and in obese CIA mice, respectively. The pathophysiologic mechanisms by which GSPE attenuates weight gain and arthritis severity in vivo were also investigated. In DIO mice, GSPE administration significantly inhibited weight gain, reduced fat infiltration in liver and improved serum lipid profiles. The antiobesity effect of GSPE was associated with increased populations of regulatory T (Treg) cells and those of decreased Th17 cells. Decrease of Th17 cells was associated with significant inhibition of their key transcriptional factors, pSTAT3Tyr705 and pSTAT3Ser727. On the contrary, GSPE-induced Treg induction was associated with enhanced pSTAT5 expression. To identify the anti-arthritis effects of GSPE, GSPE was given orally for 7 weeks after type II collagen immunization. GSPE treatment significantly attenuated the development of autoimmune arthritis in obese CIA model. In line with DIO mice, GSPE administration decreased Th17 cells and reciprocally increased Treg cells by regulating STAT proteins in autoimmune arthritis model. The expressions of pro-inflammatory cytokines and nitrotyrosine in synovium were significantly inhibited by GSPE treatment. Taken together, GSPE functions as a reciprocal regulator of T cell differentiation – suppression of Th17 cells and induction of Tregs in both DIO and obese CIA mice. GSPE may act as a therapeutic agent to treat immunologic diseases related with enhanced STAT3 activity such as metabolic disorders and autoimmune diseases.

Highlights

Grape seed proanthocyanidin extract (GSPE), a family of natural polyphenolic flavonoids, is present in a wide variety of plant foods such as fruits, berries, beans, nuts, cocoa, and wine [1]
We investigated the expressions of nitrotyrosine, a oxidative stress marker, in liver and spleen tissues of each group of mice with diet-induced obese (DIO)
Oral administration of GSPE in obese mice profoundly reduced the numbers of nitrotyrosine-expressing cells in liver as well as spleens, suggesting its antioxidative effects (Figure 1B, right panels)

Summary

Introduction

Grape seed proanthocyanidin extract (GSPE), a family of natural polyphenolic flavonoids, is present in a wide variety of plant foods such as fruits, berries, beans, nuts, cocoa, and wine [1]. GSPE treatment significantly suppressed liver lipid content, demonstrated by Oil red O staining, when compared with control DIO mice (Figure 1B, left panels). Oral administration of GSPE in obese mice profoundly reduced the numbers of nitrotyrosine-expressing cells in liver as well as spleens, suggesting its antioxidative effects (Figure 1B, right panels).

Results

Conclusion