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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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GSPE treatment decreases the expression of key pro-inflammatory molecules and modulates regulatory mediators in obese CIA mice (n = 6 for each group).(A) Representative histologic findings in joint sections from each group of mice. Joints sections were stained with anti-IL-17, anti-IL-6, anti-IL-1β, anti-TNF-α, anti-nitrotyrosine (an oxidative stress marker) antibodies and isotype (shown in brown). (B) The expressions of IL-17, RORγt, IL-21, RUNX1, SOCS3 and Foxp3 mRNA in splenocytes were determined by real-time PCR. *P<0.05, ** P<0.01 compared to the vehicle-treated group.
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pone-0078843-g004: GSPE treatment decreases the expression of key pro-inflammatory molecules and modulates regulatory mediators in obese CIA mice (n = 6 for each group).(A) Representative histologic findings in joint sections from each group of mice. Joints sections were stained with anti-IL-17, anti-IL-6, anti-IL-1β, anti-TNF-α, anti-nitrotyrosine (an oxidative stress marker) antibodies and isotype (shown in brown). (B) The expressions of IL-17, RORγt, IL-21, RUNX1, SOCS3 and Foxp3 mRNA in splenocytes were determined by real-time PCR. *P<0.05, ** P<0.01 compared to the vehicle-treated group.

Mentions: TNF-α, IL-1β, IL-6 and IL-17 are considered to be proinflammatory cytokines that are implicated in the pathogenesis of RA. We next investigated whether GSPE would affect the expression of the above molecules in the joints of obese CIA mice, by using immunohistochemistry. Compared with those of vehicle-treated group, the joints of GSPE-treated obese CIA mice demonstrated profoundly decreased cell population expressing TNF-α, IL-1β, IL-6 and IL-17 (Figure 4A). To determine the degree of oxidative damage to the joints, immunohistochemistry was used to assess the expression of nitrotyrosine on day 51 after CII immunization. The results showed that the expression of nitrotyrosine was significantly decreased in the joints of GSPE-treated obese CIA mice (Figure 4A). We examined the mRNA expressions of IL-17, RORγt, IL-21, RUNX1, SOCS3, and Foxp3 in the splenocyte isolated from both groups of mice. RUNX1 is the transcription factor that is involved in RORγt-dependent IL-17 production [27]. The mRNA expressions of IL-17, RORγt, IL-21 and RUNX1 were significantly decreased in the GSPE-treated group, whereas the expression of Foxp3 was increased. SOCS3 strongly suppresses STAT3 activity through IL-6 signaling [28]. The mRNA expression of SOCS3 tended to increase in GSPE-treated group, although the difference did not reach statistical significance (Figure 4B).


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)

GSPE treatment decreases the expression of key pro-inflammatory molecules and modulates regulatory mediators in obese CIA mice (n = 6 for each group).(A) Representative histologic findings in joint sections from each group of mice. Joints sections were stained with anti-IL-17, anti-IL-6, anti-IL-1β, anti-TNF-α, anti-nitrotyrosine (an oxidative stress marker) antibodies and isotype (shown in brown). (B) The expressions of IL-17, RORγt, IL-21, RUNX1, SOCS3 and Foxp3 mRNA in splenocytes were determined by real-time PCR. *P<0.05, ** P<0.01 compared to the vehicle-treated group.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3818494&req=5

pone-0078843-g004: GSPE treatment decreases the expression of key pro-inflammatory molecules and modulates regulatory mediators in obese CIA mice (n = 6 for each group).(A) Representative histologic findings in joint sections from each group of mice. Joints sections were stained with anti-IL-17, anti-IL-6, anti-IL-1β, anti-TNF-α, anti-nitrotyrosine (an oxidative stress marker) antibodies and isotype (shown in brown). (B) The expressions of IL-17, RORγt, IL-21, RUNX1, SOCS3 and Foxp3 mRNA in splenocytes were determined by real-time PCR. *P<0.05, ** P<0.01 compared to the vehicle-treated group.
Mentions: TNF-α, IL-1β, IL-6 and IL-17 are considered to be proinflammatory cytokines that are implicated in the pathogenesis of RA. We next investigated whether GSPE would affect the expression of the above molecules in the joints of obese CIA mice, by using immunohistochemistry. Compared with those of vehicle-treated group, the joints of GSPE-treated obese CIA mice demonstrated profoundly decreased cell population expressing TNF-α, IL-1β, IL-6 and IL-17 (Figure 4A). To determine the degree of oxidative damage to the joints, immunohistochemistry was used to assess the expression of nitrotyrosine on day 51 after CII immunization. The results showed that the expression of nitrotyrosine was significantly decreased in the joints of GSPE-treated obese CIA mice (Figure 4A). We examined the mRNA expressions of IL-17, RORγt, IL-21, RUNX1, SOCS3, and Foxp3 in the splenocyte isolated from both groups of mice. RUNX1 is the transcription factor that is involved in RORγt-dependent IL-17 production [27]. The mRNA expressions of IL-17, RORγt, IL-21 and RUNX1 were significantly decreased in the GSPE-treated group, whereas the expression of Foxp3 was increased. SOCS3 strongly suppresses STAT3 activity through IL-6 signaling [28]. The mRNA expression of SOCS3 tended to increase in GSPE-treated group, although the difference did not reach statistical significance (Figure 4B).

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