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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.
정병하,양철우,오혜좌,Shang Guo Piao,선인오,강석휘,최선령,박훈석,최범순,최영진,박철휘,김용수,조미라 생화학분자생물학회 2011 Experimental and molecular medicine Vol.43 No.11
The aim of this study was to evaluate whether the Th17and Treg cell infiltration into allograft tissue is associated with the severity of allograft dysfunction and tissue injury in acute T cell-mediated rejection (ATCMR). Seventy-one allograft tissues with biopsy-proven ATCMR were included. The biopsy specimens were immunostained for FOXP3 and IL-17. The allograft function was assessed at biopsy by measuring serum creatinine (Scr) concentration, and by applying the modified diet in renal disease (MDRD) formula, which provides the estimated glomerular filtration rate (eGFR). The severity of allograft tissue injury was assessed by calculating tissue injury scores using the Banff classification. The average numbers of infiltrating Treg and Th17 cells were 11.6 ± 12.2 cells/mm2 and 5.6 ±8.0 cells/mm2, respectively. The average Treg/Th17 ratio was 5.6 ± 8.2. The Treg/Th17 ratio was significantly associated with allograft function (Scr and MDRD eGFR) and with the severity of interstitial injury and tubular injury (P < 0.05, all parameters). In separate analyses of the number of infiltrating Treg and Th17 cells,Th17 cell infiltration was significantly associated with allograft function and the severity of tissue injury. By contrast, Treg cell infiltration was not significantly associated with allograft dysfunction or the severity of tissue injury. The results of this study show that higher infiltration of Th17 cell compared with Treg cell is significantly associated with the severity of allograft dysfunction and tissue injury.
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.
장은경,윤지희,조미라,오혜좌 대한면역학회 2011 Immune Network Vol.11 No.5
Background: CD4^+Fop3^+ regulatory T cells (Tregs) are needed to maintain peripheral tolerance, but their role in the development of autoimmune arthritis is still debated. The present study was undertaken to investigate the mechanism by which Tregs influence autoimmune arthritis, using a mouse model entitled K/BxN. Methods: We generated Treg-deficient K/BxNsf mice by congenically crossing K/BxN mice with Foxp3 mutant scurfy mice. The arthritic symptoms of the mice were clinically and histopathologically examined. The proportions and activation of CD4^+ T cells and/or dendritic cells were assessed in the spleens, draining lymph nodes and synovial tissue of these mice. Results: K/BxNsf mice exhibited earlier onset and more aggressive progression of arthritis than their K/BxN littermates. In particular, bone destruction associated with the influx of numerous RANKL+cells into synovia was very prominent. They also contained more memory phenotype CD4^+ T cells, more Th1 and Th2cells, and fewer Th17 cells than their control counterparts. Plasmacytoid dendritic cells expressing high levels of CD86and CD40 were elevated in the K/BxNsf synovia. Conclusion: We conclude that Tregs oppose the progression of arthritis by inhibiting the development of RANKL+ cells,homeostatically proliferating CD4^+ T cells, Th1, Th2 and mature plasmacytoid dendritic cells, and by inhibiting their influx into joints.
홍연식,문수진,주영빈,전찬홍,조미라,주지현,오혜좌,허유정,박성환,김호연,민준기 대한의학회 2011 Journal of Korean medical science Vol.26 No.9
The interleukin-33 (IL-33)/ST2 pathway has emerged as an intercellular signaling system that participates in antigen–allergen response, autoimmunity and fibrosis. It has been suggested that IL-33/ST2 signaling has been involved in the pathogenesis of rheumatoid arthritis (RA), because IL-33 and its receptor have been specifically mapped to RA synovium. The aim of this study was to determine the levels of IL-33 and sST2 in sera and synovial fluids in patients with RA. The serum level of IL-33 was significantly higher in patients with RA (294.9 ± 464.0 pg/mL) than in healthy controls (96.0 ± 236.9 pg/mL,P = 0.002). The synovial fluid level of IL-33 was significantly higher in RA patients than in osteoarthritis patients. The level of serum sST2 was higher in RA patients than in healthy controls (P = 0.042). A significant relationship was found between the levels of IL-33 and IL-1β (r = 0.311, P = 0.005), and IL-33 and IL-6 (r = 0.264, P = 0.017) in 81 RA patients. The levels of IL-33, sST2 and C-reactive protein decreased after conventional diseasemodifying antirheumatic drugs treatment in 10 patients with treatment-naïve RA. Conclusively, IL-33 is involved in the pathogenesis of RA and may reflect the degree of inflammation in patients with RA.
Grape seed proanthocyanidin extract ameliorates monosodium iodoacetate-induced osteoarthritis
우윤주,조미라,주영빈,정영옥,주지현,오혜좌,전주연,박미경,박진실,강창민,성미숙,박성환,김호연,민준기 생화학분자생물학회 2011 Experimental and molecular medicine Vol.43 No.10
Osteoarthritis (OA) is an age-related joint disease that is characterized by degeneration of articular cartilage and chronic pain. Oxidative stress is considered one of the pathophysiological factors in the progression of OA. We investigated the effects of grape seed proanthocyanidin extract (GSPE), which is an antioxidant, on monosodium iodoacetate (MIA)-induced arthritis of the knee joint of rat, which is an animal model of human OA. GSPE (100 mg/kg or 300 mg/kg) or saline was given orally three times per week for 4 weeks after the MIA injection. Pain was measured using the paw withdrawal latency (PWL), the paw withdrawal threshold (PWT) and the hind limb weight bearing ability. Joint damage was assessed using histological and microscopic analysis and microcomputerized tomography. Matrix metalloproteinase-13 (MMP13) and nitrotyrosine were detected using immunohistochemistry. Administration of GSPE to the MIA-treated rats significantly increased the PWL and PWT and this resulted in recovery of hind paw weight distribution (P < 0.05). GSPE reduced the loss of chondrocytes and proteoglycan,the production of MMP13, nitrotyrosine and IL-1β and the formation of osteophytes, and it reduced the number of subchondral bone fractures in the MIA-treated rats. These results indicate that GSPE is antinociceptive and it is protective against joint damage in the MIA-treated rat model of OA. GSPE could open up novel avenues for the treatment of OA.
류마티스관절염 활막세포에서 IL-10의 ERK와 AP-1 신호 전달 분자 조절을 통한 VEGF 억제
이선영 ( Seon Yeong Lee ),조미라 ( Mi La Cho ),박미경 ( Mi Kyung Park ),오혜좌 ( Hye Jwa Oh ),박성환 ( Sung Hwan Park ),김호연 ( Ho Youn Kim ) 대한류마티스학회 2009 대한류마티스학회지 Vol.16 No.3
Objective: Interleukin (IL)-10 has been demonstrated to have anti-inflammatory and anti-tumour activity. Because aberrant angiogenesis is a significant pathogenic component of tumor growth and chronic inflammation, we investigated the effect of IL-10 on the production of vascular endothelial growth factor (VEGF) by the synovial fibroblasts derived from the patients with rheumatoid arthritis (RA). Methods: Fibroblast-like synoviocytes (FLS) were cultured with transforming growth factor (TGF-β) alone or with IL-10. The level of VEGF was measured by RT-PCR and enzyme-linked immunosorbent assay (using the 24, 48 and 72 h culture supernatants). The FLSs were cultured with TGF-b for 48 hr in the presence of PD98059 (an ERK inhibitor), curcumin and SP600125 (a JNK and Ap-1 inhibitor, respectively). The level of VEGF in the supernatants was measured by ELISA. Cell viability was assessed using MTT assay. The expressions of VEGF, ERK, AP-1 and IL-10 in the synovial tissue were quantified by immunohistochemistry. Results: IL-10 exhibited the inhibitory effect on VEGF production when the FLSs were stimulated with TGF-β. ERK and AP-1 inhibitors inhibited the TGF-β induced VEGF production. Moreover, TGF-β increased the phosphorylation of ERK and C-Jun, which was significantly inhibited by the IL-10. Conclusion: IL-10 may exert an antiangiogenic effect by inhibiting the ERK- and AP-1 mediated VEGF expression in rheumatoid synovial fibroblasts.
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.