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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.
류마티스관절염 환자의 활액 세포에서 IL-17과 $IL-1{\beta}$에 의한 IL-23p19의 발현 증가
조미라,허유정,오혜좌,강창민,이선영,홍연식,김호연,Cho, Mi-La,Heo, Yu-Jung,Oh, Hye-Jwa,Kang, Chang-Min,Lee, Seon-Yeong,Hong, Yeon-Sik,Kim, Ho-Youn 대한면역학회 2008 Immune Network Vol.8 No.1
Interleukin-23 (IL-23) is a novel pro-inflammatory cytokine which has been implicated to play a pathogenic role in rheumatoid arthritis (RA). This study was undertaken to investigate the IL-23 inductive activity of the proinflammatory cytokine IL-17, $IL-1{\beta}$ and tumor necrosis factor (TNF-${\alpha}$) in RA synovial fluid mononuclear cells (SFMC). Expression of IL-23p19, IL-17, $IL-1{\beta}$ and TNF-${\alpha}$ in joint was examined by immunohistochemistry (IHC) of patients with RA and osteoarthritis (OA). The effects of IL-17 and $IL-1{\beta}$ on expression of IL-23p19 in human SFMC from RA patients were determined by reverse transcriptase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA). IL-23p19 was expressed in the RA fibroblast like synoviocyte (FLS), but not from OA FLS. Similar to the protein expression, IL-23p19 mRNA could be detected by RT-PCR in RA SFMC. IL-17 and $IL-1{\beta}$ could induce RA SFMC to produce the IL-23p19. The effects of IL-17 were much stronger than $IL-1{\beta}$ or TNF-${\alpha}$. These responses were observed in a doseresponsive manner. In addition, IL-17 or $IL-1{\beta}$ neutralizing antibody down-regulated the expression of IL-23p19 induced by LPS in RA-SFMC. Our results demonstrate that IL-23p19 is overexpressed in RA synovium and IL-17 and $IL-1{\beta}$ appears to upregulate the expression of IL-23p19 in RA-SFMC.
류마티스관절염 활막세포에서 NF-${\kappa}B$ 신호전달을 통한 MIF의 SDF-1 생성 유도
조미라,박미경,김경운,오혜좌,이선영,박진실,허유정,주지현,민준기,이상헌,박성환,김호연,Cho, Mi-La,Park, Mi-Kyung,Kim, Kyoung-Woon,Oh, Hye-Jwa,Lee, Seon-Yeong,Park, Jin-Sil,Heo, Yu-Jung,Ju, Ji-Hyeon,Min, Jun-Ki,Lee, Sang-Heon,Park, Sung-Hwa 대한면역학회 2007 Immune Network Vol.7 No.1
Background: 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-${\kappa}B$. 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-${\kappa}B$-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.
조미라,허유정,박진실,이선영,성영철,김호연,Cho, Mi-La,Heo, Yu-Jung,Park, Jin-Sil,Lee, Seon-Yeong,Sung, Young-Chul,Kim, Ho-Youn 대한면역학회 2007 Immune Network Vol.7 No.1
Autoimmune arthritis, such as rheumatoid arthritis (RA), is a chronic inflammatory disorder that primarily affects the joints and then results in their progressive destruction. Effector Th cells have been classified as Th1 and Th2 subsets based on their cytokine expression profiles and immune regulatory function. Another subset of T cells termed Th17 was recendy discovered and known to selectively produce IL-17. Also, Th17 was shown to be generated by TGF${\beta}$ and IL-6 and maintained by IL-23. IL-17 is a proinflammatory cytokine that is considered to involve the development of various inflammatory autoimmune diseases such as RA, asthma, lupus, and allograft rejection. IL-17 is present in the sera, synovial fluids and synovial biopsies of most RA patient. IL-17 activates RA synovial fibroblasts to synthesize IL-6, IL-8 and VEGF via PI3K/Akt and NF-${\kappa}B$ dependent pathway. IL-17 increases IL-6 production, collagen destruction and collagen synthesis. In addition, it not only causes bone resorption but also increases osteoclastogenesis and fetal cartilage destruction. Inhibition of the IL-17 production may contribute a novel therapeutic approach along with potent anti-inflammatory effect and with less immunosuppressive effect on host defenses.
류마티스 관절염 환자에서 Conserved T 세포 수용체의 CDR3 motif를 표현하는 제2형 콜라겐 특이 T세포주의 형성과 유지
김승훈,조미라,윤지희,박성환,조철수,황수연,김호연,Kim, Seung-Hoon,Cho, Mi-La,Youn, Jeehee,Park, Sung-Hwan,Hwang, Sue-Yun,Cho, Chul-Soo,Kim, Ho-Youn 대한면역학회 2001 Immune Network Vol.1 No.1
Background: To determine the molecular structure of type II collagen-specific T-cell receptors associated with rheumatoid arthritis (RA). Methods: We generated CII-specific T-cell lines of 8 RA patients by prolonged in vitro culture with bovine CII (bCII) and the immunogenic peptide (256-270) of human CII. The proliferation response towards CII stimulation was measured from the uptake of 3H-thymidine. Changes in the secretion of Th 1 and Th2 cytokines in the culture supernatent were measured by ELISA. The TCR clonotypes of these T-cells were examined by RT-PCR/SSCP analyses of all 22 $V_{\beta}$ chains. Results: T-cells from patients' tissue exhibited strong proliferation index upon CII stimulation, which was maintained up to 6 months in the culture. The secretion of INF-$\gamma$from these T-cells increased along with the duration of culture time, while the amount of IL-4 production did not show significant changes. The SSCP band patterns of patients' T-cells appear as discrete bands unlike the smeary streak produced from normal samples. Some SSCP bands, each representing selected expansion of a TCR containing certain subtype of $V_{\beta}$ peptides, appeared to be identical in more than one patients. Among these, the expansion of SSCP band representing the $V_{\beta}$ 14 CDR3 region persisted after switching the antigen to the immunogenic human peptide (256-270). Conclusion: CII-reactive T-cells expressing distinct CDR3 motifs are selectively expanded in the peripheral blood and synovial fluid of RA patients, and their persistent proliferation upon CII stimulation, as well as the production Th 1-type cytokines, may play pivotal roles in RA pathogenesis.
김경운,조미라,이상헌,민소연,박미경,박성환,주대명,김호연,Kim, Kyoung-Woon,Cho, Mi-La,Lee, Sang-Heon,Min, So-Youn,Park, Mi Kyung,Park, Sung-Hwan,Jue, Dae-Myung,Kim, Ho-Youn 대한면역학회 2003 Immune Network Vol.3 No.4
Inflammatory mediators has been recognized as an important role in the pathogenesis of rheumatoid arthritis (RA). IL-17 is increasingly recognized as an important regulator of immune and inflammatory responses, including induction of proinflammatory cytokines and osteoclastic bone resorption. Evidence of the expression and proinflammatory activity of IL-17 has been demonstrated in RA synovium and in animal models of RA. However, the signaling pathways that regulate IL-17 production remain unknown. In the present study, we investigated the role of the phosphatidylinositol 3 kinase (PI3K)-Akt pathway in the regulation of IL-17 production in RA. PBMC were separated from RA (n=24) patients, and stimulated with various agents (anti CD3, anti CD28, PHA, ConA, IL-15). IL-17 levels were determined by sandwich ELISA and RT-PCR. The production of IL-17 was significantly increased in cells treated with anti-CD3 antibody, PHA, IL-15 or MCP-1 (P<0.05). ConA also strongly induced IL-17 production (P<0.001), whereas TNF-alpha, IL-1beta, IL-18 or TGF-beta did not. IL-17 was detected in the PBMC of patients with osteoarthritis (OA) but their expression levels were much lower than those of RA PBMC. Anti-CD3 antibody activated the PI3K-Akt pathway and activation of the PI3K-Akt pathway resulted in a pronounced augmentation of nuclear factor kappaB ($NF-{\kappa}B$). IL-17 production by activated PBMC in RA is completely or partially blocked in the presence of $NF-{\kappa}B$ inhibitor PDTC and PI3K-Akt inhibitor, wortmannin and LY294002, respectively. Whereas the inhibition of AP-1 and extracellular signal-regulated kinase (ERK)1/2 did not affect IL-17 production. These results provide new insight into that PI3K/Akt and $NF-{\kappa}B$ dependent signal transduction pathway could be involved in the overproduction of key inflammatory cytokine, IL-17 in rheumatoid arthritis.
박민정,Mi-La Cho,Hyun-Sil Park,Hye-Joa Oh,윤보영,임정연,조미라,조석구 생화학분자생물학회 2012 Experimental and molecular medicine Vol.44 No.11
IL-17-producing CD4+ T cells (Th17) play important functions in autoimmune diseases and allograft rejection of solid organs. We examined the effects of IL 17 and its mechanism of action on arthritis in a murine collagen-induced arthritis (CIA) model using bone marrow transplantation (BMT) system. DBA/1J mice were administered a lethal radiation dose and then rescued with bone marrow derived from either wild-type (WT) or IL-17-/- mice on C57BL/6 background mice. CIA was induced after the bone marrow transplant, and disease progression was characterized. DBA/1J mice with CIA that received IL-17-/- donor bone marrow showed potently inhibited development and severity of clinical arthritis as compared with CIA mice that received WT bone marrow. Reduced secretion of the pro-inflammatory cytokines tumor necrosis factor-α,IL-1β, and IL-6, and collagen-specific T cell responses were observed in mice that received IL-17-/- bone marrow. IL-17 blockade also inhibited effector T cell proliferation by reciprocally regulating the Treg/Th17ratio. IL-17 blockade prevented joint destruction in mice with CIA. These findings suggest that CIA with BMT is a viable method of immunological manipulation and that IL-17 deficiency suppresses severe joint destruction and inflammation in CIA mice. There may be clinical benefits in blocking IL-17 and BMT in the treatment of rheumatoid arthritis.
Estrogen이 전신홍반루푸스 환자 B세포의 DNA Methylation에 미치는 영향
박미경 ( Mi Kyung Park ),박성환 ( Sung Hwan Park ),곽승기 ( Seung Ki Kwok ),조미라 ( Mi La Cho ),김호연 ( Ho Youn Kim ) 대한류마티스학회 2007 대한류마티스학회지 Vol.14 No.1
Objective: Epigenetics is an important, alternative mechanism of gene regulation that is independent of the nucleotide sequences of DNA. We investigated mRNA levels for DNA methyltransferase-1 (DNMT-1), and the effect of estrogen on the expression of DNMT-1 level in T cells and B cells from patients with systemic lupus erythematosus (SLE) and healthy subjects, and assessed the possible etiological role of DNA methylation in the pathogenesis of SLE. Methods: mRNA levels for DNMT-1 in CD4+ T cells and CD19+ B cells from 37 patients with SLE and 12 healthy controls were examined using RT-PCR. We used specific primer for DNMT-1 and β actin, The effect of estrogen on the DNA methylation was measured by the mRNA level of DNMT-1 CD4+ T cells and CD19+ B cells treated with 100 nM of 17 β-estradiol for 72 hour. Results: The levels of DNMT-1 mRNA were significantly lower in CD4+ T cells and CD19+ B cells from SLE patients compared with healthy controls. We observed the suppression of the levels of DNMT-1 mRNA by stimulated with estrogen in patients with SLE patients, especially in CD19+B cells. DNA hypomethylation of B cells was tend to be correlated with the level of anti-ds DNA antibody without statistical significance (r=-0.43, p=0.3). Conclusion: Our observations suggest that suppression of DNMT-1 by estrogen in B cells from patients with SLE might be related to the pathogenesis of SLE. Epigenetic studies may provide clues for developing new treatment strategies of SLE.