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EGCG attenuates autoimmune arthritis by inhibition of STAT3 and HIF-1α with Th17/Treg control.

Yang EJ, Lee J, Lee SY, Kim EK, Moon YM, Jung YO, Park SH, Cho ML - PLoS ONE (2014)

Bottom Line: Epigallocatechin-3-gallate (EGCG) is a green tea polyphenol exerting potent anti-oxidant and anti-inflammatory effects by inhibiting signaling and gene expression.In vitro, p-STAT3 (Y705) and p-STAT3 (S727), HIF1α and glycolytic pathway molecules were decreased by EGCG.EGCG suppressed the activation of mTOR and subsequently HIF-1α, which is considered as a metabolic check point of Th17/Treg differentiation supporting the therapeutic potential of EGCG in autoimmune arthritis.

View Article: PubMed Central - PubMed

Affiliation: The Rheumatism Research Center, Catholic Research Institute of Medical Science, The Catholic University of Korea, Seoul, South Korea ; Laboratory of Immune Network, Conversant Research Consortium in Immunologic Disease, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, South Korea.

ABSTRACT
Epigallocatechin-3-gallate (EGCG) is a green tea polyphenol exerting potent anti-oxidant and anti-inflammatory effects by inhibiting signaling and gene expression. The objective of the study was to evaluate the effect of EGCG on interleukin (IL)-1 receptor antagonist knockout (IL-1RaKO) autoimmune arthritis models. IL-1RaKO arthritis models were injected intraperitoneally with EGCG three times per week after the first immunization. EGCG decreased the arthritis index and showed protective effects against joint destruction in the IL-1RaKO arthritis models. The expression of pro-inflammatory cytokines, oxidative stress proteins, and p-STAT3 (Y705) and p-STAT3 (S727), mTOR and HIF-1α were significantly lower in mice treated with EGCG. EGCG reduced osteoclast markers in vivo and in vitro along with anti-osteoclastic activity was observed in EGCG-treated IL-1RaKO mice. The proportion of Foxp3(+) Treg cells increased in the spleens of mice treated with EGCG, whereas the proportion of Th17 cells reduced. In vitro, p-STAT3 (Y705) and p-STAT3 (S727), HIF1α and glycolytic pathway molecules were decreased by EGCG. EGCG suppressed the activation of mTOR and subsequently HIF-1α, which is considered as a metabolic check point of Th17/Treg differentiation supporting the therapeutic potential of EGCG in autoimmune arthritis.

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Treatment with EGCG suppresses inflammatory arthritis in IL-1RaKO mice.IL-1RaKO mice were immunized with 100 µg of Cll in CFA to induce arthritis. The mice were intraperitoneally injected with saline or EGCG (40 mg//kg) three times per week for 2.5 weeks. (A) Disease severity was recorded using the mean arthritis score ± SD (left) and arthritis incidence (right). (B) Tissue sections from the joints of each mouse were stained with H&E, toluidine blue and safranin O. (C) Tissue sections from the joints from the IL-1RaKO mice treated with EGCG (n = 10) or untreated (n = 10) were stained with TRAP. The histopathologic score of osteoclast formation is shown in the right graph. (D) TRAP staining for identification of osteoclasts. Osteoclast precursors were cultured in the presence of EGCG with M-CSF and RANKL. TRAP+ cells containing three or more nuclei were scored as osteoclast. TRAP+ cells were counted three times by blind scoring. (E) The levels of IgG2a or CII-specific IgG2a were measured in serum obtained from both groups of mice by ELISA. (F) T cell proliferative responses were determined in a mixed lymphocyte reaction by a [3H]thymidine incorporation assay Data represent the mean ± SD of three independent experiments or representative of more than three independent experiments (*P<0.05, **P<0.01 and ***P<0.001).
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pone-0086062-g001: Treatment with EGCG suppresses inflammatory arthritis in IL-1RaKO mice.IL-1RaKO mice were immunized with 100 µg of Cll in CFA to induce arthritis. The mice were intraperitoneally injected with saline or EGCG (40 mg//kg) three times per week for 2.5 weeks. (A) Disease severity was recorded using the mean arthritis score ± SD (left) and arthritis incidence (right). (B) Tissue sections from the joints of each mouse were stained with H&E, toluidine blue and safranin O. (C) Tissue sections from the joints from the IL-1RaKO mice treated with EGCG (n = 10) or untreated (n = 10) were stained with TRAP. The histopathologic score of osteoclast formation is shown in the right graph. (D) TRAP staining for identification of osteoclasts. Osteoclast precursors were cultured in the presence of EGCG with M-CSF and RANKL. TRAP+ cells containing three or more nuclei were scored as osteoclast. TRAP+ cells were counted three times by blind scoring. (E) The levels of IgG2a or CII-specific IgG2a were measured in serum obtained from both groups of mice by ELISA. (F) T cell proliferative responses were determined in a mixed lymphocyte reaction by a [3H]thymidine incorporation assay Data represent the mean ± SD of three independent experiments or representative of more than three independent experiments (*P<0.05, **P<0.01 and ***P<0.001).

Mentions: We first investigated whether treatment with EGCG would suppress the arthritic inflammation and joint destruction in CIA mice of IL-1Ra deficient BALB/c background. Results showed a reduction of the arthritic score and arthritis incidence when the mice were treated with an intraperitoneal injection of EGCG (40 mg/kg) when compared to the vehicle injection (Figure 1A). Histological examination demonstrated that the arthritic joints of the EGCG treated mice had a lower degree of inflammation and cartilage damage compared to the vehicle treated mice (Figure 1B). The number of TRAP-positive cells, which were regarded as osteoclasts, was markedly lower in the arthritic joints of EGCG treated mice than those of vehicle treated mice (Figure 1C). To confirm the suppressive effect of EGCG on osteoclastogenesis in vitro, the isolated BMM cells were differentiated into osteoclasts with M-CSF and RANKL in the presence or absence of EGCG at various concentrations. As shown in Figure 1D, the addition of EGCG during the induction of osteoclastogenesis significantly inhibited osteoclast formation in a dose-dependent manner. Consistently, the serum levels of the IgG2a and CII-specific IgG2a was significantly lower in the mice treated with EGCG and T cell proliferation, represented by the [3H] thymidine incorporation assay, was markedly suppressed in T cells obtained from EGCG treated mice compared to those from vehicle treated controls (Figure 1E and F)


EGCG attenuates autoimmune arthritis by inhibition of STAT3 and HIF-1α with Th17/Treg control.

Yang EJ, Lee J, Lee SY, Kim EK, Moon YM, Jung YO, Park SH, Cho ML - PLoS ONE (2014)

Treatment with EGCG suppresses inflammatory arthritis in IL-1RaKO mice.IL-1RaKO mice were immunized with 100 µg of Cll in CFA to induce arthritis. The mice were intraperitoneally injected with saline or EGCG (40 mg//kg) three times per week for 2.5 weeks. (A) Disease severity was recorded using the mean arthritis score ± SD (left) and arthritis incidence (right). (B) Tissue sections from the joints of each mouse were stained with H&E, toluidine blue and safranin O. (C) Tissue sections from the joints from the IL-1RaKO mice treated with EGCG (n = 10) or untreated (n = 10) were stained with TRAP. The histopathologic score of osteoclast formation is shown in the right graph. (D) TRAP staining for identification of osteoclasts. Osteoclast precursors were cultured in the presence of EGCG with M-CSF and RANKL. TRAP+ cells containing three or more nuclei were scored as osteoclast. TRAP+ cells were counted three times by blind scoring. (E) The levels of IgG2a or CII-specific IgG2a were measured in serum obtained from both groups of mice by ELISA. (F) T cell proliferative responses were determined in a mixed lymphocyte reaction by a [3H]thymidine incorporation assay Data represent the mean ± SD of three independent experiments or representative of more than three independent experiments (*P<0.05, **P<0.01 and ***P<0.001).
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pone-0086062-g001: Treatment with EGCG suppresses inflammatory arthritis in IL-1RaKO mice.IL-1RaKO mice were immunized with 100 µg of Cll in CFA to induce arthritis. The mice were intraperitoneally injected with saline or EGCG (40 mg//kg) three times per week for 2.5 weeks. (A) Disease severity was recorded using the mean arthritis score ± SD (left) and arthritis incidence (right). (B) Tissue sections from the joints of each mouse were stained with H&E, toluidine blue and safranin O. (C) Tissue sections from the joints from the IL-1RaKO mice treated with EGCG (n = 10) or untreated (n = 10) were stained with TRAP. The histopathologic score of osteoclast formation is shown in the right graph. (D) TRAP staining for identification of osteoclasts. Osteoclast precursors were cultured in the presence of EGCG with M-CSF and RANKL. TRAP+ cells containing three or more nuclei were scored as osteoclast. TRAP+ cells were counted three times by blind scoring. (E) The levels of IgG2a or CII-specific IgG2a were measured in serum obtained from both groups of mice by ELISA. (F) T cell proliferative responses were determined in a mixed lymphocyte reaction by a [3H]thymidine incorporation assay Data represent the mean ± SD of three independent experiments or representative of more than three independent experiments (*P<0.05, **P<0.01 and ***P<0.001).
Mentions: We first investigated whether treatment with EGCG would suppress the arthritic inflammation and joint destruction in CIA mice of IL-1Ra deficient BALB/c background. Results showed a reduction of the arthritic score and arthritis incidence when the mice were treated with an intraperitoneal injection of EGCG (40 mg/kg) when compared to the vehicle injection (Figure 1A). Histological examination demonstrated that the arthritic joints of the EGCG treated mice had a lower degree of inflammation and cartilage damage compared to the vehicle treated mice (Figure 1B). The number of TRAP-positive cells, which were regarded as osteoclasts, was markedly lower in the arthritic joints of EGCG treated mice than those of vehicle treated mice (Figure 1C). To confirm the suppressive effect of EGCG on osteoclastogenesis in vitro, the isolated BMM cells were differentiated into osteoclasts with M-CSF and RANKL in the presence or absence of EGCG at various concentrations. As shown in Figure 1D, the addition of EGCG during the induction of osteoclastogenesis significantly inhibited osteoclast formation in a dose-dependent manner. Consistently, the serum levels of the IgG2a and CII-specific IgG2a was significantly lower in the mice treated with EGCG and T cell proliferation, represented by the [3H] thymidine incorporation assay, was markedly suppressed in T cells obtained from EGCG treated mice compared to those from vehicle treated controls (Figure 1E and F)

Bottom Line: Epigallocatechin-3-gallate (EGCG) is a green tea polyphenol exerting potent anti-oxidant and anti-inflammatory effects by inhibiting signaling and gene expression.In vitro, p-STAT3 (Y705) and p-STAT3 (S727), HIF1α and glycolytic pathway molecules were decreased by EGCG.EGCG suppressed the activation of mTOR and subsequently HIF-1α, which is considered as a metabolic check point of Th17/Treg differentiation supporting the therapeutic potential of EGCG in autoimmune arthritis.

View Article: PubMed Central - PubMed

Affiliation: The Rheumatism Research Center, Catholic Research Institute of Medical Science, The Catholic University of Korea, Seoul, South Korea ; Laboratory of Immune Network, Conversant Research Consortium in Immunologic Disease, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, South Korea.

ABSTRACT
Epigallocatechin-3-gallate (EGCG) is a green tea polyphenol exerting potent anti-oxidant and anti-inflammatory effects by inhibiting signaling and gene expression. The objective of the study was to evaluate the effect of EGCG on interleukin (IL)-1 receptor antagonist knockout (IL-1RaKO) autoimmune arthritis models. IL-1RaKO arthritis models were injected intraperitoneally with EGCG three times per week after the first immunization. EGCG decreased the arthritis index and showed protective effects against joint destruction in the IL-1RaKO arthritis models. The expression of pro-inflammatory cytokines, oxidative stress proteins, and p-STAT3 (Y705) and p-STAT3 (S727), mTOR and HIF-1α were significantly lower in mice treated with EGCG. EGCG reduced osteoclast markers in vivo and in vitro along with anti-osteoclastic activity was observed in EGCG-treated IL-1RaKO mice. The proportion of Foxp3(+) Treg cells increased in the spleens of mice treated with EGCG, whereas the proportion of Th17 cells reduced. In vitro, p-STAT3 (Y705) and p-STAT3 (S727), HIF1α and glycolytic pathway molecules were decreased by EGCG. EGCG suppressed the activation of mTOR and subsequently HIF-1α, which is considered as a metabolic check point of Th17/Treg differentiation supporting the therapeutic potential of EGCG in autoimmune arthritis.

Show MeSH
Related in: MedlinePlus