Grape seed proanthocyanidin extract-mediated regulation of STAT3 proteins contributes to Treg differentiation and attenuates inflammation in a murine model of obesity-associated arthritis.

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, pSTAT3(Tyr705) and pSTAT3(Ser727). 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.

• Authors: Joo Yeon Jhun, Su-Jin Moon, Bo Young Yoon, Jae Kyung Byun, Eun Kyung Kim, Eun Ji Yang, Ji Hyeon Ju, Yeon Sik Hong, Jun Ki Min, Sung Hwan Park, Ho Youn Kim, Mi-La Cho
• Journal: PloS one (PLoS One) Vol. 8 Issue 11 Pg. e78843 ( 2013) ISSN: 1932-6203 [Electronic] United States
• PMID: 24223854 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cytokines
• Grape Seed Extract
• Inflammation Mediators
• Proanthocyanidins
• STAT3 Transcription Factor
• proanthocyanidin

Topics

• Administration, Oral
• Animals
• Arthritis (complications, prevention & control)
• Arthritis, Experimental (complications, prevention & control)
• Cell Differentiation (drug effects)
• Cytokines (genetics, metabolism)
• Diet, High-Fat (adverse effects)
• Disease Models, Animal
• Gene Expression (drug effects)
• Grape Seed Extract (administration & dosage, pharmacology)
• Humans
• Inflammation (complications, prevention & control)
• Inflammation Mediators (metabolism)
• Mice, Inbred C57BL
• Microscopy, Confocal
• Obesity (complications, etiology, prevention & control)
• Proanthocyanidins (administration & dosage, pharmacology)
• Reverse Transcriptase Polymerase Chain Reaction
• STAT3 Transcription Factor (metabolism)
• T-Lymphocytes, Regulatory (drug effects, metabolism, pathology)
• Th17 Cells (drug effects, metabolism, pathology)