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Keun hyung Cho,Hyun-Sik Na,JooYeon Jhun,Jiyoung Kim,Seung Yoon Lee,Jeong soo Lee,In Gyu Um,Seok Jung Kim,Mi-La Cho 한국실험동물학회 2021 한국실험동물학회 학술발표대회 논문집 Vol.2021 No.7
Osteoarthritis (OA) is a disease that reduces quality of life due to pain caused by persistent joint destruction. In addition, as a representative chronic disease, it causes inflammation and affects immunity, and it is one of the diseases that is difficult to cure, so treatment and improvement methods are urgently needed. In a previous study, we published that LA-1 improves osteoarthritis and has cartilage protection by controlling inflammation. However, it was not known how LA-1 improves osteoarthritis in the body. So in this study, it was confirmed that the administration of LA-1 to the MIA-induced OA rat model reduces the pain threshold, protects cartilage, and regulates inflammation markers in the articular synovium. Additionally, collecting and analyzing the feces of the disease model, it affected the gastrointestinal system and improved the environment of the microbiome. Interestingly, by providing LA-1, it was confirmed that the diversity and abundance of microbiome in the intestine were changed, and that the bacteria that produced SCFAs increased. In addition, daily supply of butyrate, one of the SCFAs produced by certain bacteria, triggers autophagy activation and tends to decrease necroptosis. This suggests that systemic immunity as well as OA is regulated according to changes in the intestinal microbial community, and that activation of autophagy can indirectly reduce abnormal cell death. In addition, assuming that osteoarthritis is a chronic degenerative disease, cell analysis was performed using splenocyte and blood assuming that the immune system is deteriorated. As a result, both splenocytes and PBMCs confirmed that regulatory T cells increased and Th17 cells decreased. In summary, providing LA-1 leads to increased production of SCFAs by altering the microbes in the intestine. Accordingly, it is possible to suppress the progression of OA and control pain due to OA, and improve an abnormal joint environment by controlling autophagy and necroptosis.
Cho, Seok Goo,Min, So-Youn,Park, Min Jung,Lee, Kyung Wha,Cho, Young-Gyu,Cho, Mi-La,Chang, Hong Seok,Park, Se-Ho,Lee, Jong Wook,Min, Woo Sung,Kim, Chun Choo,Kim, Ho-Youn Wiley Subscription Services, Inc., A Wiley Company 2006 Vol.54 No.6
<B>Objective</B><P>To investigate the immunoregulatory effects of allogeneic mixed chimerism induced by T cell–depleted, nonmyeloablative bone marrow transplantation (BMT) on chronic inflammatory arthritis and autoimmunity in mice deficient in interleukin-1 receptor antagonist (IL-1Ra).</P><B>Methods</B><P>IL-1Ra<SUP>−/−</SUP> mice (H-2K<SUP>d</SUP>) were treated with antibody to asialoganglioside G<SUB>M1</SUB> (anti–natural killer cell), total body irradiation (500 cGy), and T cell–depleted, nonmyeloablative BMT derived from C57BL/6 mice (H-2K<SUP>b</SUP>). Engraftment and chimerism were evaluated in peripheral blood, lymph nodes, and spleen by multicolor flow cytometry. The severity of arthritis was evaluated by clinical scoring and histopathologic assessment. Levels of IgG1 and IgG2a subtypes of anti–type II collagen (anti-CII) antibodies were measured in serum samples. After T cells were stimulated with CII, ovalbumin, and phytohemagglutinin, T cell proliferative responses and levels of cytokine production (interferon-γ [IFNγ], tumor necrosis factor α [TNFα], interleukin-10 [IL-10], and IL-17) were assayed in culture supernatants.</P><B>Results</B><P>All IL-1Ra<SUP>−/−</SUP> mice receiving BMT showed marked improvement in arthritis within 3 weeks, as well as successful induction of mixed chimerism. These mice showed higher levels of IgG1, and lower levels of IgG2a anti-CII antibodies and weaker T cell proliferative responses than did mice in the control groups (either no treatment or conditioning alone without bone marrow rescue). In mixed chimeras, the levels of IFNγ, TNFα, and IL-17 produced from CII-stimulated T cells were significantly suppressed and IL-10 production was significantly higher as compared with controls.</P><B>Conclusion</B><P>The introduction of allogeneic mixed chimerism showed a strong immunoregulatory potential to correct established chronic inflammatory arthritis and autoimmunity originating from a dysregulated proinflammatory cytokine network.</P>
Cho, Mi-La,Kang, Jung-Won,Moon, Young-Mee,Nam, Hyo-Jung,Jhun, Joo-Yeon,Heo, Seong-Beom,Jin, Hyun-Tak,Min, So-Youn,Ju, Ji-Hyeon,Park, Kyung-Su,Cho, Young-Gyu,Yoon, Chong-Hyeon,Park, Sung-Hwan,Sung, You American Association of Immunologists 2006 Journal of Immunology Vol.176 No.9
<P>IL-23 is a heterodimeric cytokine composed of a p19 subunit and the p40 subunit of IL-12. IL-23 has proinflammatory activity, inducing IL-17 secretion from activated CD4(+) T cells and stimulating the proliferation of memory CD4(+) T cells. We investigated the pathogenic role of IL-23 in CD4(+) T cells in mice lacking the IL-1R antagonist (IL-1Ra(-/-)), an animal model of spontaneous arthritis. IL-23 was strongly expressed in the inflamed joints of IL-1Ra(-/-) mice. Recombinant adenovirus expressing mouse IL-23 (rAd/mIL-23) significantly accelerated this joint inflammation and joint destruction. IL-1beta further increased the production of IL-23, which induced IL-17 production and OX40 expression in splenic CD4(+) T cells of IL-1Ra(-/-) mice. Blocking IL-23 with anti-p19 Ab abolished the IL-17 production induced by IL-1 in splenocyte cultures. The process of IL-23-induced IL-17 production in CD4(+) T cells was mediated via the activation of Jak2, PI3K/Akt, STAT3, and NF-kappaB, whereas p38 MAPK and AP-1 did not participate in the process. Our data suggest that IL-23 is a link between IL-1 and IL-17. IL-23 seems to be a central proinflammatory cytokine in the pathogenesis of this IL-1Ra(-/-) model of spontaneous arthritis. Its intracellular signaling pathway could be useful therapeutic targets in the treatment of autoimmune arthritis.</P>
Park, Mi-Kyung,Oh, Hye-Jwa,Heo, Yang-Mi,Park, Eun-Mi,Cho, Mi-La,Kim, Ho-Youn,Park, Sung-Hwan Korean Society for Biochemistry and Molecular Bion 2011 Experimental and molecular medicine Vol.43 No.8
Indoleamine 2,3-dioxygenase (IDO) is a key negative regulator of immune responses and has been implicated in tumor tolerance, autoimmune disease and asthma. IDO was detected in the joint synovial tissue in the inflammatory microenvironment of rheumatoid arthritis (RA), but IDO expression in joint synovial tissue is not sufficient to overcome the inflamed synovial environment. This study aimed to unravel the mechanisms involving the failure to activate tolerogenic IDO in the inflamed joint. We demonstrate that both poly (I:C) and lipopolysaccharide (LPS) induce expression of IDO in synovial fibroblasts. However, inflammatory cytokines such as IL-17, TNF-${\alpha}$, IL-12, IL-23 and IL-16 did not induce IDO expression. Poly (I:C) appeared to induce higher IDO expression than did LPS. Surprisingly, toll-like receptor (TLR)4-mediated IDO expression was upregulated after depletion of myeloid differentiation primary response protein 88 (MyD88) in synovial fibroblasts using small interfering RNA (siRNA). IDO, TLR3 and TLR4 were highly expressed in synovial tissue of RA patients compared with that of osteoarthritis patients. In addition, RA patients with severe disease activity had higher levels of expression of IDO, TLR3 and TLR4 in the synovium than patients with mild disease activity. These data suggest that upregulation of IDO expression in synovial fibroblasts involves TLR3 and TLR4 activation by microbial constituents. We showed that the mechanisms responsible for IDO regulation primarily involve MyD88 signaling in synovial fibroblasts, as demonstrated by siRNA-mediated knockdown of MyD88.
류마티스관절염 활막세포에서 NF-κB 신호전달을 통한 MIF의 SDF-1 생성 유도
조미라(Cho, Mi-La),박미경(Park, Mi-Kyung),김경운(Kim, Kyoung-Woon),오혜좌(Oh, Hye-Jwa),이선영(Lee, Seon-Yeong),박진실(Park, Jin-Sil),허유정(Heo, Yu-Jung),주지현(Ju, Ji-Hyeon),민준기(Min, Jun-Ki),이상헌(Lee, Sang-Heon),박성환(Park, Su 대한면역학회 2007 Immune Network Vol.7 No.1
Stromal cell-derived factor (SDF)-1 is a potent chemoattractant for activated T cells into the inflamed Rheumatoid arthritis (RA) synovium. To determine the effect of macrophage migration inhibitory factor (MIF) on the production of SDF-1 in the inflamed RA synovium. Methods: The expression of SDF-1 and MIF in RA and Osteoarthritis (OA) synovium was examined by immunohistochemical staining. The SDF-1 was quantified by RT-PCR and ELISA after RA fibroblast like synoviocyte (FLS) were treated with MIF in the presence and absence of inhibitors of intracellular signal molecules. The synovial fluid (SF) and serum levels of MIF and SDF-1 in RA, OA and healthy control were measured by ELISA. Results: Expression of SDF-1 and MIF in synovium was higher in RA patients than in OA patients. The production of SDF-1 was enhanced in RA FLS by MIF stimulation. Such effect of MIF was blocked by the inhibitors of NF-κB . Concentrations of SDF-1 in the serum and SF were higher in RA patients than in OA patients and healthy control. SDF-1 and MIF was overexpressed in RA FLS, and MIF could up-regulate the production of SDF-1 in RA FLS via NF-κB -mediated pathways. Conclusion: These results suggest that an inhibition of interaction between MIF from T cells and SDF-1 of FLS may provide a new therapeutic approach in the treatment of RA.