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Therapeutic effect of baicalin on experimental autoimmune encephalomyelitis is mediated by SOCS3 regulatory pathway.

Zhang Y, Li X, Ciric B, Ma CG, Gran B, Rostami A, Zhang GX - Sci Rep (2015)

Bottom Line: Natural compounds derived from medicinal plants have long been considered a rich source of novel therapeutic agents.Ba treatment effectively ameliorated clinical disease severity in myelin oligodendrocyte glycoprotein (MOG)35-55 peptide-induced EAE, and reduced inflammation and demyelination of the central nervous system (CNS).Taken together, our findings demonstrate that Ba has significant potential as a novel anti-inflammatory agent for therapy of autoimmune diseases such as MS.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, Thomas Jefferson University, Philadelphia, PA, USA.

ABSTRACT
Natural compounds derived from medicinal plants have long been considered a rich source of novel therapeutic agents. Baicalin (Ba) is a bioactive flavonoid compound derived from the root of Scutellaria baicalensis, an herb widely used in traditional medicine for the treatment of various inflammatory diseases. In this study, we investigate the effects and mechanism of action of Ba in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). Ba treatment effectively ameliorated clinical disease severity in myelin oligodendrocyte glycoprotein (MOG)35-55 peptide-induced EAE, and reduced inflammation and demyelination of the central nervous system (CNS). Ba reduced infiltration of immune cells into the CNS, inhibited expression of proinflammatory molecules and chemokines, and prevented Th1 and Th17 cell differentiation via STAT/NFκB signaling pathways. Further, we showed that SOCS3 induction is essential to the effects of Ba, given that the inhibitory effect of Ba on pathogenic Th17 responses was largely abolished when SOCS3 signaling was knocked down. Taken together, our findings demonstrate that Ba has significant potential as a novel anti-inflammatory agent for therapy of autoimmune diseases such as MS.

No MeSH data available.


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Induction of SOCS3 underlies inhibition of Th17 cell differentiation by Ba.(a) SOCS3 expression was determined by real-time PCR in CD4+ T cells from spleens of Ba- or PBS-treated EAE mice (left), or in naïve CD4+ cells under Th17 cell differentiation conditions at different concentrations of Ba (middle) and harvested at time points indicated, with a concentration of Ba at 20 μg/ml (right). (b) SOCS3 promoter activity was determined in CD4+ T cells transfected with a 1619-bp murine SOCS3 promoter-GFP reporter in the presence of Ba (5–20 μg/ml). GFP expression and production were determined by RT-PCR and flow cytometry. (c) SOCS3 (left) and RORγt (right) expression in CD4+ T cells transfected with SOCS3-specific or control LV-siRNAs under Th17 cell polarization conditions in the presence or absence of Ba (20 μg/ml). IL-17 A production (d) and STAT3 phosphorylation (e) were measured by flow cytometry and ELISA in CD4+ T cells cultured in conditions described in C. Data are expressed as mean ± SEM. (n = 5). *P < 0.05; **P < 0.01; ***P < 0.001. One representative of three experiments is shown.
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f7: Induction of SOCS3 underlies inhibition of Th17 cell differentiation by Ba.(a) SOCS3 expression was determined by real-time PCR in CD4+ T cells from spleens of Ba- or PBS-treated EAE mice (left), or in naïve CD4+ cells under Th17 cell differentiation conditions at different concentrations of Ba (middle) and harvested at time points indicated, with a concentration of Ba at 20 μg/ml (right). (b) SOCS3 promoter activity was determined in CD4+ T cells transfected with a 1619-bp murine SOCS3 promoter-GFP reporter in the presence of Ba (5–20 μg/ml). GFP expression and production were determined by RT-PCR and flow cytometry. (c) SOCS3 (left) and RORγt (right) expression in CD4+ T cells transfected with SOCS3-specific or control LV-siRNAs under Th17 cell polarization conditions in the presence or absence of Ba (20 μg/ml). IL-17 A production (d) and STAT3 phosphorylation (e) were measured by flow cytometry and ELISA in CD4+ T cells cultured in conditions described in C. Data are expressed as mean ± SEM. (n = 5). *P < 0.05; **P < 0.01; ***P < 0.001. One representative of three experiments is shown.

Mentions: Next, we investigated the upstream signaling events involved in the alteration of Th1/Th17 responses by Ba. Given that suppressor of cytokine signaling 3 (SOCS3) plays an important role in inhibiting Th17 response30 as well as Th1 response31, we tested if SOCS3 plays a role in the effects of Ba. Indeed, upon Ba treatment, SOCS3 expression was increased in CD4+ T cells in Ba-treated EAE mice both in vivo (Fig. 7a, left) and in vitro (Fig. 7a, middle and right). The basal level of SOCS3 expression was detected during Th17 polarization, while its expression was significantly elevated by Ba in a dose-dependent manner (approximately 6~10-fold higher). Upon 20 μg/ml treatment, SOCS3 expression was up-regulated as early as 1 h, continued to peak at 4 h and remained elevated for at least 24 h.


Therapeutic effect of baicalin on experimental autoimmune encephalomyelitis is mediated by SOCS3 regulatory pathway.

Zhang Y, Li X, Ciric B, Ma CG, Gran B, Rostami A, Zhang GX - Sci Rep (2015)

Induction of SOCS3 underlies inhibition of Th17 cell differentiation by Ba.(a) SOCS3 expression was determined by real-time PCR in CD4+ T cells from spleens of Ba- or PBS-treated EAE mice (left), or in naïve CD4+ cells under Th17 cell differentiation conditions at different concentrations of Ba (middle) and harvested at time points indicated, with a concentration of Ba at 20 μg/ml (right). (b) SOCS3 promoter activity was determined in CD4+ T cells transfected with a 1619-bp murine SOCS3 promoter-GFP reporter in the presence of Ba (5–20 μg/ml). GFP expression and production were determined by RT-PCR and flow cytometry. (c) SOCS3 (left) and RORγt (right) expression in CD4+ T cells transfected with SOCS3-specific or control LV-siRNAs under Th17 cell polarization conditions in the presence or absence of Ba (20 μg/ml). IL-17 A production (d) and STAT3 phosphorylation (e) were measured by flow cytometry and ELISA in CD4+ T cells cultured in conditions described in C. Data are expressed as mean ± SEM. (n = 5). *P < 0.05; **P < 0.01; ***P < 0.001. One representative of three experiments is shown.
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Related In: Results  -  Collection

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f7: Induction of SOCS3 underlies inhibition of Th17 cell differentiation by Ba.(a) SOCS3 expression was determined by real-time PCR in CD4+ T cells from spleens of Ba- or PBS-treated EAE mice (left), or in naïve CD4+ cells under Th17 cell differentiation conditions at different concentrations of Ba (middle) and harvested at time points indicated, with a concentration of Ba at 20 μg/ml (right). (b) SOCS3 promoter activity was determined in CD4+ T cells transfected with a 1619-bp murine SOCS3 promoter-GFP reporter in the presence of Ba (5–20 μg/ml). GFP expression and production were determined by RT-PCR and flow cytometry. (c) SOCS3 (left) and RORγt (right) expression in CD4+ T cells transfected with SOCS3-specific or control LV-siRNAs under Th17 cell polarization conditions in the presence or absence of Ba (20 μg/ml). IL-17 A production (d) and STAT3 phosphorylation (e) were measured by flow cytometry and ELISA in CD4+ T cells cultured in conditions described in C. Data are expressed as mean ± SEM. (n = 5). *P < 0.05; **P < 0.01; ***P < 0.001. One representative of three experiments is shown.
Mentions: Next, we investigated the upstream signaling events involved in the alteration of Th1/Th17 responses by Ba. Given that suppressor of cytokine signaling 3 (SOCS3) plays an important role in inhibiting Th17 response30 as well as Th1 response31, we tested if SOCS3 plays a role in the effects of Ba. Indeed, upon Ba treatment, SOCS3 expression was increased in CD4+ T cells in Ba-treated EAE mice both in vivo (Fig. 7a, left) and in vitro (Fig. 7a, middle and right). The basal level of SOCS3 expression was detected during Th17 polarization, while its expression was significantly elevated by Ba in a dose-dependent manner (approximately 6~10-fold higher). Upon 20 μg/ml treatment, SOCS3 expression was up-regulated as early as 1 h, continued to peak at 4 h and remained elevated for at least 24 h.

Bottom Line: Natural compounds derived from medicinal plants have long been considered a rich source of novel therapeutic agents.Ba treatment effectively ameliorated clinical disease severity in myelin oligodendrocyte glycoprotein (MOG)35-55 peptide-induced EAE, and reduced inflammation and demyelination of the central nervous system (CNS).Taken together, our findings demonstrate that Ba has significant potential as a novel anti-inflammatory agent for therapy of autoimmune diseases such as MS.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, Thomas Jefferson University, Philadelphia, PA, USA.

ABSTRACT
Natural compounds derived from medicinal plants have long been considered a rich source of novel therapeutic agents. Baicalin (Ba) is a bioactive flavonoid compound derived from the root of Scutellaria baicalensis, an herb widely used in traditional medicine for the treatment of various inflammatory diseases. In this study, we investigate the effects and mechanism of action of Ba in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). Ba treatment effectively ameliorated clinical disease severity in myelin oligodendrocyte glycoprotein (MOG)35-55 peptide-induced EAE, and reduced inflammation and demyelination of the central nervous system (CNS). Ba reduced infiltration of immune cells into the CNS, inhibited expression of proinflammatory molecules and chemokines, and prevented Th1 and Th17 cell differentiation via STAT/NFκB signaling pathways. Further, we showed that SOCS3 induction is essential to the effects of Ba, given that the inhibitory effect of Ba on pathogenic Th17 responses was largely abolished when SOCS3 signaling was knocked down. Taken together, our findings demonstrate that Ba has significant potential as a novel anti-inflammatory agent for therapy of autoimmune diseases such as MS.

No MeSH data available.


Related in: MedlinePlus