Kyung-Ah Jung

PTEN ameliorates autoimmune arthritis through down-regulating STAT3 activation with reciprocal balance of Th17 and Tregs

PTEN is a tyrosine phosphatase with significant function in inhibiting STAT3 activation. Recently, inactivation of STAT3 has been demonstrated as a therapeutic candidate for autoimmune arthritis. The expression of PTEN controlled by p53 regulates autoimmune arthritis through modulating the balance between Th17 and Treg. We hypothesized that PTEN regulated by p53 might reduce CIA severity and inflammatory response via inhibiting STAT3 activation. Our results revealed that PTEN could ameliorate experimental autoimmune arthritis by reducing STAT3 activity and Th17 differentiation. Systemic infusion of PTEN overexpression downregulated CIA severity. In addition, PTEN overexpression decreased the activation of T cells and modulated reciprocal differentiation of Th17 and Treg cells. We observed that PTEN expression downregulated by p53 deficiency induced the activation of STAT3. Loss of p53 exacerbated autoimmune arthritis and dysregulated the population of Th17 and Treg. These data suggest that induction of STAT3-modulatory activity of PTEN may be a therapeutic target for rheumatoid arthritis therapy.

STX0119 ameliorates arthritis in SKG mice via inhibiting T helper 17

Rheumatoid arthritis (RA) is an autoimmune disease with chronic and excessive inflammation. Upregulation of interleukin (IL)-17 is involved in the pathogenesis of RA. STX0119 is a specific inhibitor of signal transducer and activator of transcription 3 (STAT3) as a potential target for the treatment of RA. STAT3 is a member of DNA-binding molecules that regulates the expression of proinflammatory cytokines involved in the pathogenesis of RA. The objective of this study was to determine whether STX0119 could inhibit STAT3 and IL-17. We demonstrated that STX0119 decreased T helper (Th) 17 differentiation and IL-17 expression in vitro. STX0119 also improved the severity of zymosan induced arthritis and reduced joint inflammation. STX0119 reduced the proliferation of Th17 and phosphorylated STAT3 expression while increasing Treg differentiation and phosphorylated STAT5 expression. Moreover, STX0119 decreased the expression of IL-6 and -17 but not IL-10. These findings suggest that STX0119 can be used to treat autoimmune RA through inhibiting the activation of STAT3.

Achaete-scute complex homologue 2 accelerates the development of Sjögren’s syndrome-like disease in the NOD/ShiLtJ mouse

Achaete-scute complex homologue 2 (Ascl2) has been reported to induce the differentiation and activation of follicular helper T (TFH) cells, which are essential for development of Sjögrens syndrome (SS). This study examined whether Ascl2 plays a role in the development of SS. NOD/ShiLtJ mice were injected with an Ascl2-overexpression vector, and the infiltration of lymphocytes into salivary and lacrimal glands was assessed. The expression of inflammatory cytokines and chemoattractants for T or B cells was measured. The activation of TFH cells was assessed using a specific marker of TFH cells. Ascl2 level was also measured in SS patients. Overexpression of Ascl2 increased the expression of C-X-C chemokine receptor type 5 (CXCR5) in both salivary and lacrimal glands (p<0.0001). Overexpression of Ascl2 also increased the expression of proinflammatory cytokines and chemoattractants including interleukin 6 (IL-6), tumor necrosis factor-α, IL-8, programmed cell death 1 (PD-1), IL-21, and B-cell lymphoma 6 (Bcl-6). Overexpression of Ascl2 increased the populations of CD4+CXCR5+, CD4+ICOS+, and CD4+PD-1+ cells. The Ascl2 level was higher in peripheral blood mononuclear cells from SS patients compared with those from healthy controls. Our findings suggest that Ascl2 may play a role in the development and progression of SS and may be a therapeutic target in the treatment of SS.

Inhibition of the TWEAK/Fn14 pathway attenuates autoimmune arthritis in a SKG mouse model

Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) is a proinflammatory cytokine that is involved in pathogenesis of abnormal or disregulated inflammation. To verify how TWEAK/fibroblast growth factor-inducible gene 14 (Fn14) signals affect development of Th17 cells in arthritis, we utilized the SKG mouse, which spontaneously develops Th17-mediated autoimmune arthritis. Fn14-Fc was administered to zymosan A-induced arthritogenic SKG mice, and the effects in vivo were examined. Destruction of cartilage and bone damage was assessed by Hematoxylin and Eosin, and safranin O staining of the affected tissues. Phenotypic analysis of cells expressing inflammatory cytokines and angiogenesis-related factors, and the expression of transcription factor STAT3 in the affected joints were determined by immunohistochemistry. Blockade of Fn14 with Fn14-Fc reduced the clinical and histologic scores of inflammatory arthritis in the mouse model of spontaneously developed chronic autoimmune arthritis. Fn14-Fc suppressed production of inflammatory cytokines and angiogenesis-promoting factors, such as vascular endothelial growth factor and matrix metalloproteinase 3. Moreover, blocking of the TWEAK signal inhibited expression of STAT3 as well as interleukin-17 and -21 produced by Th17 cells. These results implicate TWEAK as a potential molecular target for treatment or prevention of inflammatory arthritis and autoimmune diseases such as rheumatoid arthritis.

A probiotic complex, rosavin, zinc, and prebiotics ameliorate intestinal inflammation in an acute colitis mouse model

BackgroundAn altered gut microbiota balance is involved in the pathogenesis of inflammatory bowel disease (IBD), and several probiotic strains are used as dietary supplements to improve intestinal health. We evaluated the therapeutic effect of 12 probiotics in combination with prebiotics, rosavin, and zinc in the dextran sodium sulfate (DSS)-induced colitis mouse model.MethodsThe probiotic complex or the combination drug was administered orally to mice with DSS-induced colitis, and the body weight, disease activity index, colon length, and histopathological parameters were evaluated. Also, the combination drug was applied to HT-29 epithelial cells, and the expression of monocyte chemoattractant protein 1 (MCP-1) was evaluated by real-time polymerase chain reaction.ResultsAdministration of the combination drug attenuated the severity of DSS-induced colitis. Moreover, the combination drug significantly reduced the levels of the proinflammatory cytokines tumor necrosis factor-α, interleukin (IL)-6, IL-1β, and IL-17, and significantly increased the levels of Foxp3 and IL-10 in colon sections. Additionally, treatment with the combination drug reduced MCP-1 expression in HT-29 cells. Treatment with the combination drug decreased the levels of α-smooth muscle actin and type I collagen compared with vehicle treatment in mice with DSS-induced colitis.ConclusionThese results suggest that the combination of a probiotic complex with rosavin, zinc, and prebiotics exerts a therapeutic effect on IBD by modulating production of pro- and anti-inflammatory cytokines and the development of fibrosis.

YinYang1 deficiency ameliorates joint inflammation in a murine model of rheumatoid arthritis by modulating Th17 cell activation

Yin Yang 1 (YY1) is a ubiquitously expressed transcription factor that functions in cooperation with various cofactors to regulate gene expression. In the immune system, YY1 enhances cytokine production and T helper (Th) 2 effector cell differentiation, resulting in the activation of inflammation. However, no studies have reported the role of YY1 in Th17 cell regulation, which is implicated in rheumatoid arthritis (RA). We investigated the expression of YY1 in Th17 cells in vitro and revealed increased levels of YY1 mRNA and protein. To elucidate the function of YY1 pathogenesis in RA, we used a collagen-induced arthritis (CIA) mouse model with YY1 deficiency. Deficiency of YY1 reduced the severity of arthritis and joint destruction. Moreover, Th17 cells were dramatically reduced in YY1-deficient mice. The cytokine interleukin (IL)-17 was decreased in YY1-deficient CD4+ T cells ex vivo and in vivo. Interestingly, the level of signal transducer and activator of transcription 3 (STAT3), tumor necrosis factor-α, IL-17, IL-6, and IL-1β were markedly decreased in YY1-deficient mice with CIA. The cytokine-inducing function of YY1 was more specific to IL-17 than to interferon-γ. YY1 plays a role in Th17 cell differentiation and RA pathogenesis. Our findings suggest that future RA therapies should target the regulatory mechanism involved in Th17 cell differentiation, in which YY1 may cooperate with the STAT3 signaling pathway.

Deficiency of IL-1 receptor antagonist suppresses IL-10-producing B cells in autoimmune arthritis in an IL-17/Th17-dependent manner

Rheumatoid arthritis (RA) is a systemic autoimmune disease with CD4+ T cell infiltration and hyperplasia of synovial tissues leading to progressive destruction of articular cartilage. In addition to the central role of T cells in the pathogenesis of RA, recent reports have suggested that B cells also contribute to RA. To explore the effects of interleukin (IL)-17 on B cell development and response in excess IL-1 signaling, we generated IL-17 and IL-1 receptor antagonist (IL-1Ra) double-deficient mice via backcrossing IL-17 knockout (KO) and IL-1RaKO mice. We studied the effect of IL-17 deficiency on antibody-producing B cells and regulatory B cells in IL-1RaKO mice. Excess IL-1 signal increased the frequency of B220+ IgG+ cells and plasma cells. It also promoted the production of immunoglobulins in vitro. Moreover, IL-17 deficiency significantly enhanced the frequency of regulatory IL-10-producing regulatory B cells in IL-1RaKO mice. IL-17 deficiency ameliorated disease symptoms of inflammatory arthritis in IL-1RaKO mice by suppressing the frequency of plasma cells and antibody production while enhancing the frequency of IL-10-producing B cells. These findings suggest that IL-17 can trigger an inflammatory immune reaction by activating antibody-producing B cells while suppressing immune regulatory B cells in RA.

IL-1-IL-17 Signaling Axis Contributes to Fibrosis and Inflammation in Two Different Murine Models of Systemic Sclerosis

Objective Systemic sclerosis (SSc) is a progressive fibrotic disease that affects the skin and internal organs. Despite evidence implicating increased interleukin-17 (IL-17) activity in SSc, the role of IL-17 in SSc remains uncertain. The purpose of this study was to investigate whether IL-17 plays a pathophysiological role in SSc in two different murine models of SSc. Methods Bleomycin (BLM)-induced fibrosis and chronic graft-versus-host disease (cGVHD) models were used. Histological analysis was performed using Masson’s trichrome and immunohistochemical staining. Quantitative reverse transcription-polymerase chain reaction and enzyme-linked immunoassays were used to quantify the messenger RNA and protein levels of inflammatory mediators in dermal fibroblasts. Results IL-1 receptor antagonist-deficient (IL-1Ra-KO) mice were more severely affected by BLM injection, as shown by dermal and pulmonary fibrosis, compared with wild-type (WT) mice. Increased tissue fibrosis was reversed by knocking down IL-17. In vitro experiments showed that IL-1 and IL-17 exerted synergistic effects on the expression of profibrotic and inflammatory mediators. In the cGVHD model, C57BL/6 mice receiving splenocytes of IL-1Ra-KO BALB/c mice developed more severe cGVHD than did those receiving cells from WT mice. Knockdown of IL-17 in IL-1Ra-KO donor mice significantly attenuated the IL-1-induced acceleration of cGVHD severity. Conclusion Targeting IL-1 and its downstream IL-17 activity may be a novel treatment strategy for inhibiting inflammation and tissue fibrosis in SSc.

Ursodeoxycholic acid attenuates experimental autoimmune arthritis by targeting Th17 and inducing pAMPK and transcriptional corepressor SMILE

BACKGROUND Ursodeoxycholic acid (UDCA) has been known that UDCA has prominent effects on liver, however, there is little known about its influence on autoimmune disease. Here, the benefit of UDCA on arthritis rheumatoid (RA) in vivo was tested. METHODS RA mouse were induced using collagen II (CIA, collagen induced arthritis) where the disease severity or UDCA-related signaling pathway such as AMP-activated protein kinase (AMPK) or small heterodimer partner interacting leucine zipper protein (SMILE) was evaluated by westerblot and immunohistochemical staining. Gene expression was measured by realtime-polymerase chain reaction (PCR). RESULTS The administration of UDCA effectively alleviated the arthritic score and incidence with decreased cartilage damage and lipid metabolic parameters. UDCA also suppressed the secretion of pro-inflammatory cytokines. It was confirmed that UDCA upregulated the expression of SMILE and transcriptional activity of PPARγ via controlling AMPK or p38 activity. CONCLUSIONS In the present study, the therapeutic effect of UDCA inducing SMILE through AMPK activation in rheumatoid arthritis mouse as well as other autoimmune disease was proposed.

Combination of Coq10, Omega 3 and Zinc Improves the Severity of Experimental Arthritis by Inhibiting the Immune-inflammatory Response

Omega 3, zinc and coenzyme Q10 (CoQ10) are used as dietary supplements revealing an anti-inflammatory function. Individually they have been recognized as important players in rheumatoid arthritis (RA). However, there is no evidence of the synergic effect of omega 3, zinc and CoQ10 in RA. This study aims to identify if omega 3, zinc and CoQ10 can improve the progression of zymosan-induced arthritis (ZIA) using a mouse model. Results showed that the combination of omega 3, zinc and CoQ10 decreased ZIA severity decreasing IgG levels, joint inflammation and cartilage damage. The combination of omega 3, zinc and CoQ10 reduced interleukin (IL)-6, -17, tumor necrosis factor (TNF)-α and interferon (IFN)-γ expression. There was also a decrease in osteoclastogenesis with the combination of omega 3, zinc and CoQ10. These observations demonstrate that the combination of omega 3, zinc and CoQ10 improved ZIA progression by reducing proinflammatory cytokines expression compared to CoQ10 alone. Thus, the combination of omega 3, zinc and CoQ10 presents as an important preventive measure in RA, which can aid in understanding in it pathogenesis.