Grape seed proanthocyanidin extract-mediated regulation of STAT3 proteins contributes to Treg differentiation and attenuates inflammation in a murine model of obesity-associated arthritis.
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.
Conversant Research Consortium in Immunologic disease, College of Medicine, The Catholic University of Korea, Seoul, South Korea ; Rheumatism Research Center, College of Medicine, The Catholic University of Korea, Seoul, South Korea.
Joo Yeon
JY
Jhun
Su-Jin
SJ
Moon
Bo Young
BY
Yoon
Jae Kyung
JK
Byun
Eun Kyung
EK
Kim
Eun Ji
EJ
Yang
Ji Hyeon
JH
Ju
Yeon Sik
YS
Hong
Jun Ki
JK
Min
Sung Hwan
SH
Park
Ho Youn
HY
Kim
Mi-La
ML
Cho
D000284:Administration, Oral; D000818:Animals; D001168:Arthritis / Q000150:complications / Q000517:prevention & control*; D001169:Arthritis, Experimental / Q000150:complications / Q000517:prevention & control; D002454:Cell Differentiation / Q000187:drug effects*; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D059305:Diet, High-Fat / Q000009:adverse effects; D004195:Disease Models, Animal; D015870:Gene Expression / Q000187:drug effects; D056604:Grape Seed Extract / Q000008:administration & dosage / Q000494:pharmacology*; D006801:Humans; D007249:Inflammation / Q000150:complications / Q000517:prevention & control; D018836:Inflammation Mediators / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018613:Microscopy, Confocal; D009765:Obesity / Q000150:complications / Q000209:etiology / Q000517:prevention & control*; D044945:Proanthocyanidins / Q000008:administration & dosage / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D058504:Th17 Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology
D016207:Cytokines; D056604:Grape Seed Extract; D018836:Inflammation Mediators; D044945:Proanthocyanidins; D050796:STAT3 Transcription Factor; C013221:proanthocyanidin