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Fraxinellone Attenuates Rheumatoid Inflammation in Mice
Jung, Seung Min,Lee, Jaeseon,Baek, Seung Ye,Lee, Juhyun,Jang, Se Gwang,Hong, Seung-Min,Park, Jin-Sil,Cho, Mi-La,Park, Sung-Hwan,Kwok, Seung-Ki MDPI 2018 INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES Vol.19 No.3
<P>This study aimed to evaluate the therapeutic effect of fraxinellone on inflammatory arthritis and identify the underlying mechanisms. Fraxinellone (7.5 mg/kg) or a vehicle control was injected into mice with collagen-induced arthritis (CIA). The severity of arthritis was evaluated clinically and histologically. The differentiation of CD4<SUP>+</SUP> T cells and CD19<SUP>+</SUP> B cells was investigated in the presence of fraxinellone. Osteoclastogenesis after fraxinellone treatment was evaluated by staining with tartrate-resistant acid phosphatase (TRAP) and by measuring the mRNA levels of osteoclastogenesis-related genes. Fraxinellone attenuated the clinical and histologic features of inflammatory arthritis in CIA mice. Fraxinellone suppressed the production of interleukin-17 and the expression of <I>RAR-related orphan receptor γ t</I> and phospho-signal transducer and activator of transcription 3 in CD4<SUP>+</SUP> T cells. CD19<SUP>+</SUP> B cells showed lower expression of <I>activation-induced cytidine deaminase</I> and <I>B lymphocyte-induced maturation protein-1</I> after treatment with fraxinellone. The formation of TRAP-positive cells and the expression of osteoclastogenesis-related markers were reduced in the presence of fraxinellone. Inhibition of interleukin-17 and osteoclastogenesis was also observed in experiments using human peripheral mononuclear cells. Fraxinellone alleviated synovial inflammation and osteoclastogenesis in mice. The therapeutic effect of fraxinellone was associated with the inhibition of cellular differentiation and activation. The data suggests that fraxinellone could be a novel treatment for inflammatory arthritis, including rheumatoid arthritis.</P>
Min, So-Youn,Park, Kyung-Su,Cho, Mi-La,Kang, Jung-Won,Cho, Young-Gyu,Hwang, Sue-Yun,Park, Min-Jung,Yoon, Chong-Hyeon,Min, Jun-Ki,Lee, Sang-Heon,Park, Sung-Hwan,Kim, Ho-Youn Wiley Subscription Services, Inc., A Wiley Company 2006 Vol.54 No.3
<B>Objective</B><P>Although oral tolerance is a well-known phenomenon, the role of dendritic cells (DCs) is not well characterized. This study was conducted to better understand the differential role played by each Peyer's patch DC subset in the induction of oral tolerance to type II collagen (CII) in murine collagen-induced arthritis (CIA).</P><B>Methods</B><P>CII was fed 6 times to DBA/1 mice beginning 2 weeks before immunization, and the effect on arthritis was assessed. We compared the proportion of CD11c+,CD11b+ DCs and CD11c+,CD8α+ DCs in the Peyer's patches of CII-fed tolerized and phosphate buffered saline–fed nontolerized mice after the induction of CIA. The immunosuppressive properties of each DC subset were determined using fluorescence-activated cell sorter analysis for intracellular interleukin-10 (IL-10) and IL-12 and mixed lymphocyte culture. The ability of each DC subset to induce CD4+,CD25+ T regulatory cells was also examined. Mice were injected with CII-pulsed CD11c+,CD11b+ DCs isolated from Peyer's patches of tolerized mice, and the effect on CIA was examined.</P><B>Results</B><P>The severity of arthritis was significantly lower in tolerized mice. The proportion of CD11c+,CD11b+ DCs was increased in the Peyer's patches of tolerized mice and those DCs exhibited immunosuppressive characteristics, such as increased IL-10 production, inhibition of T cell proliferative responses to CII, and CD4+,CD25+ regulatory T cell induction. Furthermore, the CD11c+,CD11b+ DCs suppressed the severity of arthritis upon adoptive transfer.</P><B>Conclusion</B><P>Our observations demonstrate that CD11c+,CD11b+ DCs, which are abundant in Peyer's patches during the induction of oral tolerance to CII, are crucial for the suppression of CIA and could be exploited for immunotherapy of autoimmune diseases.</P>
Jung, Chang Hee,Lee, Min Jung,Kang, Yu Mi,Jang, Jung Eun,Leem, Jaechan,Lee, Yoo La,Seol, So Mi,Yoon, Hae Kyeong,Lee, Woo Je,Park, Joong-Yeol Issued for the Endocrine Society by the Williams W 2014 The Journal of clinical endocrinology & metabolism Vol.99 No.12
<P>Although recent animal studies have suggested that C1q/TNF-related protein-9 (CTRP9) is more likely to be involved in the regulation of vascular function, more specifically atherosclerosis, in rodents, little is known about whether serum CTRP9 level is associated with atherosclerosis in humans.</P>
Park, Min-Jung,Lee, Seung Hoon,Lee, Sung-Hee,Lee, Eun-Jung,Kim, Eun-Kyung,Choi, Jong Young,Cho, Mi-La Hindawi Publishing Corporation 2015 MEDIATORS OF INFLAMMATION Vol.2015 No.-
<P>T helper (Th) 17 cells are a subset of Th cells expressing interleukin- (IL-) 17 and initiating an inflammatory response in autoimmune diseases. Graft-versus-host disease (GVHD) is an immune inflammatory disease caused by interactions between the adaptive immunity of donor and recipient. The Th17 lineage exhibits proinflammatory activity and is believed to be a central player in GVHD. IL-1 performs a key function in immune responses and induces development of Th17 cells. Here, we show that blockade of IL-1 signaling suppresses Th17 cell differentiation and alleviates GVHD severity. We hypothesized that the IL-1 receptor antagonist (IL-1Ra) would suppress Th17 cell differentiation<I> in vitro</I> via inhibition of glycolysis-related genes. Blockade of IL-1 using IL-1Ra downregulated Th17 cell differentiation, an alloreactive T cell response, and expression of genes of the glycolysis pathway. Severity of GVHD was reduced in mice with a transplant of IL-Ra-treated cells, in comparison with control mice. To clarify the mechanisms via which IL-1Ra exerts the therapeutic effect, we demonstrated<I> in vivo</I> that IL-1Ra decreased the proportion of Th17 cells, increased the proportion of FoxP3-expressing T regulatory (T<SUB>reg</SUB>) cells, and inhibited expression of glycolysis-related genes and suppressed Th17 cell development and B-cell activation. These results suggest that blockade of IL-1 signaling ameliorates GVHD via suppression of excessive T cell-related inflammation.</P>
Park, Min-Jung,Moon, Su-Jin,Baek, Jin-Ah,Lee, Eun-Jung,Jung, Kyung-Ah,Kim, Eun-Kyung,Kim, Da-Som,Lee, Jung-Ho,Kwok, Seung-Ki,Min, Jun-Ki,Kim, Seok Jung,Park, Sung-Hwan,Cho, Mi-La The American Association of Immunologists, Inc. 2019 JOURNAL OF IMMUNOLOGY Vol.203 No.1
<P><B>Key Points</B></P><P><OL><LI>Metformin enhances immunomodulatory properties and migration capacity of MSCs.</LI><LI>Metformin-treated MSCs exert therapeutic property in OA rats.</LI></OL></P><P>Mesenchymal stem cells (MSCs) can protect against cartilage breakdown in osteoarthritis (OA) via their immunomodulatory capacities. However, the optimization strategy for using MSCs remains challenging. This study’s objective was to identify the in vivo effects of metformin-stimulated adipose tissue-derived human MSCs (Ad-hMSCs) in OA. An animal model of OA was established by intra-articular injection of monosodium iodoacetate into rats. OA rats were divided into a control group and two therapy groups (treated with Ad-hMSCs or metformin-stimulated Ad-hMSCs). Limb nociception was assessed by measuring the paw withdrawal latency and threshold. Our data show that metformin increased IL-10 and IDO expression in Ad-hMSCs and decreased high-mobility group box 1 protein, IL-1β, and IL-6 expression. Metformin increased the migration capacity of Ad-hMSCs with upregulation of chemokine expression. In cocultures, metformin-stimulated Ad-hMSCs inhibited the mRNA expression of RUNX2, COL X, VEGF, MMP1, MMP3, and MMP13 in IL-1β–stimulated OA chondrocytes and increased the expression of TIMP1 and TIMP3. The antinociceptive activity and chondroprotective effects were greater in OA rats treated with metformin-stimulated Ad-hMSCs than in those treated with unstimulated Ad-hMSCs. TGF-β expression in subchondral bone of OA joints was attenuated more in OA rats treated with metformin-stimulated Ad-hMSCs. Our findings suggest that metformin offers a promising option for the clinical application of Ad-hMSCs as a cell therapy for OA.</P>
( Hong Ki Min ),( Seon Yeong Lee ),( Jin Young Kang ),( Jung Hee Koh ),( Ji Yeon Lee ),( Jennifer Lee ),( Seung Min Jung ),( Seung Ki Kwok ),( Ji Hyeon Ju ),( Wan Uk Kim ),( Mi La Cho ),( Sung Hwan Pa 대한내과학회 2014 대한내과학회 추계학술발표논문집 Vol.2014 No.1
Background: IL-1ß signalling plays a key role in the pathogenesis of various infi ammatory arthritis conditions including rheumatoid arthritis (RA). We investigated the therapeutic effects of a human IL-1 receptor antagonist with Fc fragment (“hIL-1Ra- Fc”) on autoimmune arthritis and assessed the possible mechanism(s) by which hIL-1Ra- Fc exerts anti-arthritic effects in a murine model of RA and patients with rheumatoid arthritis. Methods: A collagen-induced arthritis (CIA) murine model was induced in DBA/1J mice. Levels of various cytokines were determined using enzyme-linked immunosorbent assays. Joints of the mice were assessed for clinical arthritis scores and histological features. Th17 cells and Treg cells were stained using antibodies specifi c for CD4, IL-17, CD25, and FoxP3. Osteoclastogenesis was assessed using TRAP staining and real-time PCR. Results: hIL-1Ra-Fc reduced the arthritis incidence, histological infi ammation, and cartilage scores in the CIA model. The expression of pro-infi ammatory cytokines, VEGF and RANKL, was reduced in affected joints of hIL-1Ra-Fc-treated mice. hIL-1Ra-Fc-treated mice showed decreased numbers of Th17 cells, with increased Treg cells in spleens. hIL- 1Ra-Fc reduced Th17 cell differentiation by inactivation of STAT3 signalling, reciprocallyinducing Treg cell differentiation through STAT5 signalling. Additionally, expression of the IL-17, TNF-a, RANKL, and VEGF genes decreased, while FoxP3 gene expression was increased in the PBMCs of RA patients after administration of hIL-1Ra-Fc. Conclusions: The anti-arthritis effects of hIL-1Ra-Fc are associated with regulating balance between Th17 cells and Treg cells and with suppressing osteoclastogenesis and angiogenesis in affected joints.