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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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Reciprocal effects of GSPE on Th17 and Foxp3+ Treg cells population in obesity induced by a HFD.(A) Spleen tissues from each mouse 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×). Each confocal image is representative of five fields of view and three separate experiments. 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 (right upper panel). The populations of Th17 and Treg cells in spleens of each group of mice were determined by flow cytometry (right lower panel). *P<0.05, **P<0.01 versus the control 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 (red) (right image). The cell populations were analyzed using laser confocal microscopy (original magnification, 400×). The graphs show the number of positive cells (lower panel). Values are the means ± SD. ***P<0.001 compared to the control mice.
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pone-0078843-g002: Reciprocal effects of GSPE on Th17 and Foxp3+ Treg cells population in obesity induced by a HFD.(A) Spleen tissues from each mouse 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×). Each confocal image is representative of five fields of view and three separate experiments. 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 (right upper panel). The populations of Th17 and Treg cells in spleens of each group of mice were determined by flow cytometry (right lower panel). *P<0.05, **P<0.01 versus the control 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 (red) (right image). The cell populations were analyzed using laser confocal microscopy (original magnification, 400×). The graphs show the number of positive cells (lower panel). Values are the means ± SD. ***P<0.001 compared to the control mice.

Mentions: We enumerated CD4+CD25+Foxp3+ Treg cells and CD4+IL-17+ Th17 cells in spleen tissues from DIO mice treated with or without GSPE. The results demonstrated that spleen tissues from obese mice treated with GSPE showed increases in the number of Foxp3+ Treg cells and reciprocally decreases in the number of Th17 cells, compared with control DIO mice (Figure 2A). The results of the flow cytometric analysis are consistent with those of confocal study. STAT3 is an essential transcription factor that is involved in Th17 differentiation, activation, proliferation and survival [23]. Hence, the expression levels of STAT3 and its phosphorylated forms in splenocytes were evaluated. The confocal microscopy results demonstrated that the expression of both STAT3 phosphorylated at tyrosine 705 (pSTAT3Tyr705) and STAT3 phosphorylated at serine 707 (pSTAT3Ser705) were decreased by treatment with GSPE (Figure 2B). On the opposite side of STAT3, STAT5 is the major transcription factor for the differentiation of Treg cells that function to inhibit the proliferation and function of CD4+ T cells [24]–[26]. STAT5 activity among the CD4+ T cells in spleens was significantly increased by GSPE treatment (Figure 2B). Taken together, oral administration of GSPE in mice with obesity induced by high-fat diet resulted in significant suppression on Th17 cells and reciprocal induction of Treg cells. That results were associated with modulation of STAT 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)

Reciprocal effects of GSPE on Th17 and Foxp3+ Treg cells population in obesity induced by a HFD.(A) Spleen tissues from each mouse 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×). Each confocal image is representative of five fields of view and three separate experiments. 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 (right upper panel). The populations of Th17 and Treg cells in spleens of each group of mice were determined by flow cytometry (right lower panel). *P<0.05, **P<0.01 versus the control 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 (red) (right image). The cell populations were analyzed using laser confocal microscopy (original magnification, 400×). The graphs show the number of positive cells (lower panel). Values are the means ± SD. ***P<0.001 compared to the control mice.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3818494&req=5

pone-0078843-g002: Reciprocal effects of GSPE on Th17 and Foxp3+ Treg cells population in obesity induced by a HFD.(A) Spleen tissues from each mouse 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×). Each confocal image is representative of five fields of view and three separate experiments. 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 (right upper panel). The populations of Th17 and Treg cells in spleens of each group of mice were determined by flow cytometry (right lower panel). *P<0.05, **P<0.01 versus the control 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 (red) (right image). The cell populations were analyzed using laser confocal microscopy (original magnification, 400×). The graphs show the number of positive cells (lower panel). Values are the means ± SD. ***P<0.001 compared to the control mice.
Mentions: We enumerated CD4+CD25+Foxp3+ Treg cells and CD4+IL-17+ Th17 cells in spleen tissues from DIO mice treated with or without GSPE. The results demonstrated that spleen tissues from obese mice treated with GSPE showed increases in the number of Foxp3+ Treg cells and reciprocally decreases in the number of Th17 cells, compared with control DIO mice (Figure 2A). The results of the flow cytometric analysis are consistent with those of confocal study. STAT3 is an essential transcription factor that is involved in Th17 differentiation, activation, proliferation and survival [23]. Hence, the expression levels of STAT3 and its phosphorylated forms in splenocytes were evaluated. The confocal microscopy results demonstrated that the expression of both STAT3 phosphorylated at tyrosine 705 (pSTAT3Tyr705) and STAT3 phosphorylated at serine 707 (pSTAT3Ser705) were decreased by treatment with GSPE (Figure 2B). On the opposite side of STAT3, STAT5 is the major transcription factor for the differentiation of Treg cells that function to inhibit the proliferation and function of CD4+ T cells [24]–[26]. STAT5 activity among the CD4+ T cells in spleens was significantly increased by GSPE treatment (Figure 2B). Taken together, oral administration of GSPE in mice with obesity induced by high-fat diet resulted in significant suppression on Th17 cells and reciprocal induction of Treg cells. That results were associated with modulation of STAT 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