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

Jhun JY, Moon SJ, Yoon BY, Byun JK, Kim EK, Yang EJ, Ju JH, Hong YS, Min JK, Park SH, Kim HY, Cho ML - PLoS ONE (2013)

Bottom Line: 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).To identify the anti-arthritis effects of GSPE, GSPE was given orally for 7 weeks after type II collagen immunization.

View Article: PubMed Central - PubMed

Affiliation: 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.

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.

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Treatment with GSPE decreased Th17 through in vivo regulation of pSTAT3Tyr705 and pSTAT3Ser727 and reciprocally increased Foxp3+ Treg cells through pSTAT5 induction in obese CIA mice (n = 6 for each group).(A) Spleen tissues from each group of mice were stained for CD4+CD25+Foxp3+ Treg cells and CD4+IL-17+ Th17 cells using monoclonal antibodies against CD4 (red), CD25 (blue), and Foxp3 (green) (left image) or CD4 (green) and IL-17 (red) (right image) (original magnification, 400×). CD4+CD25+Foxp3+ T cells and CD4+IL-17+ T cells were enumerated visually at higher magnification (projected on a screen) by four individuals, and the mean values are presented in the form of a histogram. **P<0.01, ***P<0.001 versus the vehicle-treated group. (B) Spleens from mice in each group were examined by immunofluorescence staining with monoclonal antibodies against CD4 (green) and pSTAT3Tyr705 (red) (left image), or CD4 (green) and pSTAT3Ser727 (red) (middle image), or CD4 (green) and pSTAT5 (right image) (original magnification, 400×). The CD4+pSTAT3Tyr705, CD4+pSTAT3Ser727 and CD4+pSTAT5+ cells were analyzed using laser confocal microscopy and the numbers of the cells were enumerated visually at higher magnification (projected on a screen) by four individuals. The mean values are presented in the form of a histogram. ***P<0.001 compared to the vehicle control mice.
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pone-0078843-g005: Treatment with GSPE decreased Th17 through in vivo regulation of pSTAT3Tyr705 and pSTAT3Ser727 and reciprocally increased Foxp3+ Treg cells through pSTAT5 induction in obese CIA mice (n = 6 for each group).(A) Spleen tissues from each group of mice were stained for CD4+CD25+Foxp3+ Treg cells and CD4+IL-17+ Th17 cells using monoclonal antibodies against CD4 (red), CD25 (blue), and Foxp3 (green) (left image) or CD4 (green) and IL-17 (red) (right image) (original magnification, 400×). CD4+CD25+Foxp3+ T cells and CD4+IL-17+ T cells were enumerated visually at higher magnification (projected on a screen) by four individuals, and the mean values are presented in the form of a histogram. **P<0.01, ***P<0.001 versus the vehicle-treated group. (B) Spleens from mice in each group were examined by immunofluorescence staining with monoclonal antibodies against CD4 (green) and pSTAT3Tyr705 (red) (left image), or CD4 (green) and pSTAT3Ser727 (red) (middle image), or CD4 (green) and pSTAT5 (right image) (original magnification, 400×). The CD4+pSTAT3Tyr705, CD4+pSTAT3Ser727 and CD4+pSTAT5+ cells were analyzed using laser confocal microscopy and the numbers of the cells were enumerated visually at higher magnification (projected on a screen) by four individuals. The mean values are presented in the form of a histogram. ***P<0.001 compared to the vehicle control mice.

Mentions: To ascertain whether or not GSPE treatment in mice with obese CIA can control Th17/Treg cell population, each population of those T cell subset was assessed. The results showed a larger population of Foxp3+ Treg cells in GSPE-treated arthritis mice. In contrast with that, IL-17 expressing CD4+ T cells (mainly Th17 cells) were significantly decreased by treatment with GSPE (Figure 5A). In line with the results in DIO mice, GSPE treatment in arthritis mice also exhibited attenuated expressions of STAT3 activity (both pSTAT3Tyr705 and pSTAT3Ser727) in CD4+ T cells, whereas pSTAT5 activity in those cells was profoundly augmented (Figure 5B). We conclude that GSPE diverted differentiation of CD4+ T cells toward a Treg phenotype in murine model of obesity-associated autoimmune arthritis through a modulation of STAT3 proteins.


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

Jhun JY, Moon SJ, Yoon BY, Byun JK, Kim EK, Yang EJ, Ju JH, Hong YS, Min JK, Park SH, Kim HY, Cho ML - PLoS ONE (2013)

Treatment with GSPE decreased Th17 through in vivo regulation of pSTAT3Tyr705 and pSTAT3Ser727 and reciprocally increased Foxp3+ Treg cells through pSTAT5 induction in obese CIA mice (n = 6 for each group).(A) Spleen tissues from each group of mice were stained for CD4+CD25+Foxp3+ Treg cells and CD4+IL-17+ Th17 cells using monoclonal antibodies against CD4 (red), CD25 (blue), and Foxp3 (green) (left image) or CD4 (green) and IL-17 (red) (right image) (original magnification, 400×). CD4+CD25+Foxp3+ T cells and CD4+IL-17+ T cells were enumerated visually at higher magnification (projected on a screen) by four individuals, and the mean values are presented in the form of a histogram. **P<0.01, ***P<0.001 versus the vehicle-treated group. (B) Spleens from mice in each group were examined by immunofluorescence staining with monoclonal antibodies against CD4 (green) and pSTAT3Tyr705 (red) (left image), or CD4 (green) and pSTAT3Ser727 (red) (middle image), or CD4 (green) and pSTAT5 (right image) (original magnification, 400×). The CD4+pSTAT3Tyr705, CD4+pSTAT3Ser727 and CD4+pSTAT5+ cells were analyzed using laser confocal microscopy and the numbers of the cells were enumerated visually at higher magnification (projected on a screen) by four individuals. The mean values are presented in the form of a histogram. ***P<0.001 compared to the vehicle control mice.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3818494&req=5

pone-0078843-g005: Treatment with GSPE decreased Th17 through in vivo regulation of pSTAT3Tyr705 and pSTAT3Ser727 and reciprocally increased Foxp3+ Treg cells through pSTAT5 induction in obese CIA mice (n = 6 for each group).(A) Spleen tissues from each group of mice were stained for CD4+CD25+Foxp3+ Treg cells and CD4+IL-17+ Th17 cells using monoclonal antibodies against CD4 (red), CD25 (blue), and Foxp3 (green) (left image) or CD4 (green) and IL-17 (red) (right image) (original magnification, 400×). CD4+CD25+Foxp3+ T cells and CD4+IL-17+ T cells were enumerated visually at higher magnification (projected on a screen) by four individuals, and the mean values are presented in the form of a histogram. **P<0.01, ***P<0.001 versus the vehicle-treated group. (B) Spleens from mice in each group were examined by immunofluorescence staining with monoclonal antibodies against CD4 (green) and pSTAT3Tyr705 (red) (left image), or CD4 (green) and pSTAT3Ser727 (red) (middle image), or CD4 (green) and pSTAT5 (right image) (original magnification, 400×). The CD4+pSTAT3Tyr705, CD4+pSTAT3Ser727 and CD4+pSTAT5+ cells were analyzed using laser confocal microscopy and the numbers of the cells were enumerated visually at higher magnification (projected on a screen) by four individuals. The mean values are presented in the form of a histogram. ***P<0.001 compared to the vehicle control mice.
Mentions: To ascertain whether or not GSPE treatment in mice with obese CIA can control Th17/Treg cell population, each population of those T cell subset was assessed. The results showed a larger population of Foxp3+ Treg cells in GSPE-treated arthritis mice. In contrast with that, IL-17 expressing CD4+ T cells (mainly Th17 cells) were significantly decreased by treatment with GSPE (Figure 5A). In line with the results in DIO mice, GSPE treatment in arthritis mice also exhibited attenuated expressions of STAT3 activity (both pSTAT3Tyr705 and pSTAT3Ser727) in CD4+ T cells, whereas pSTAT5 activity in those cells was profoundly augmented (Figure 5B). We conclude that GSPE diverted differentiation of CD4+ T cells toward a Treg phenotype in murine model of obesity-associated autoimmune arthritis through a modulation of STAT3 proteins.

Bottom Line: 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).To identify the anti-arthritis effects of GSPE, GSPE was given orally for 7 weeks after type II collagen immunization.

View Article: PubMed Central - PubMed

Affiliation: 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.

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.

Show MeSH
Related in: MedlinePlus