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류마티스 섬유모세포양 활막세포에서 저산소증이 시토카인 생산에 미치는 영향
안중경 ( Joong Kyung Ahn ),전찬홍 ( Chan Hong Jeon ),고재현 ( Jae Hyun Koh ),김진희 ( Jin Hee Kim ),최화정 ( Hwa Jung Choi ),안광성 ( Kwang Sung Ahn ),차훈석 ( Hoon Suk Cha ),유석희 ( Suk Hee Yu ),고은미 ( Eun Mi Koh ) 대한류마티스학회 2003 대한류마티스학회지 Vol.10 No.1
Objective: Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by increased production of cytokines, proliferation of fibroblast-like synoviocytes (FLS) and joint destruction. It is well known that the involved joints in RA are hypoxic. Hypoxia may play a role in the pathogenesis of RA. We thought that hypoxia might alter the production of cytokines by FLS and these changes could affect the biologic behaviors of FLS. Based on that, we investigated whether hypoxia affects the production of cytokines in FLS and the effect of these changes on matrix metalloproteinases (MMPs) expression. Methods: Fibroblast-like synoviocytes from human rheumatoid synovial tissue obtained duringjoint replacement surgery were cultured in vitro. Hypoxic culture was performed by incubating cells in BBL(R) Gaspak pouch(TM) anaerobic system. After incubation under hypoxic condition for 24 hr, the concentrations of various cytokines in culture supernatants were determined by ELISA. To determine the effect of highly expressed cytokines on MMP expression, we performed ELISA of MMP-1, MMP-2 and MMP-3 in cultured FLS, after stimulation with respective cytokines. Results: In hypoxic state, IL-6, IL-8 and vascular endothelial growth factor (VEGF) concentrations were significantly increased compared to those in normoxic condition. However, there were little differences in IL-1, IL-2, IL-4, TNF-α and TGF-β. Stimulation of FLS with IL-6 and IL-8 showed the increased concentrations of MMP-1, MMP-2 and MMP-3. Conclusion: Hypoxic environment of rheumatoid synovium might affect FLS to produce proinflammatory and proangiogenic cytokine such as IL-6 and IL-8. These cytokines again could stimulate MMPs production in FLS leading to joint destruction.
차훈석 ( Hoon Suk Cha ),전찬홍 ( Chan Hong Jeon ),최화정 ( Hwa Jung Choi ),안광성 ( Kwang Sung Ahn ),송영욱 ( Yeong Wook Song ),고은미 ( Eun Mi Koh ) 대한류마티스학회 2003 대한류마티스학회지 Vol.10 No.2
Objective: The rheumatoid synovium is a hypoxic environment and hypoxia has been implicated to have a role in the pathogenesis of rheumatoid arthritis (RA). In this work, we tried to investigate the effect of hypoxia on the expression of matrix metalloproteinase (MMP)-1, -3 and tissue inhibitor of metalloproteinase (TIMP)-1 in rheumatoid and osteoarthritis (OA) fibroblast-like synoviocytes (FLS). Methods: FLS obtained from RA and OA patients were cultured under normoxic or hypoxic condition for 48 hours. Western blot analyses for MMP-1, -3 and TIMP-1 were performed. TIMP-1 mRNA levels were measured by Northern blot analysis. Results: Hypoxia increased MMP-1 expression in rheumatoid FLS compared with normoxia. TIMP-1 expression was decreased by hypoxia in rheumatoid FLS in both protein and mRNA levels. On the other hand, hypoxia did not significantly affect MMP-1, -3 and TIMP-1 expressions in OA FLS. Conclusion: These results suggest that microenvironment such as hypoxia may directly contribute to joint destruction in RA by increasing the ratio of MMP-1 to TIMP-1 production in FLS.
전찬홍 ( Chan Hong Jeon ),김진희 ( Jin Hee Kim ),박정호 ( Jung Ho Park ),안광성 ( Kwang Sung Ahn ),김형진 ( Hyung Jin Kim ),김응호 ( Eung Ho Kim ),안중경 ( Joong Kyong Ahn ),차훈석 ( Hoon Suk Cha ),고은미 ( Eun Mi Koh ) 대한내과학회 2003 대한내과학회지 Vol.64 No.5
목적 : 관절염의 진단과 임상양상에 따른 관절 활액내 사이토카인의 농도 차이 및 특징적 양태를 보기 위하여 류마티스 관절염 환자와 골관절염 환자의 활액에서 TNF-α 와 가용성 TNF 수용체 1, 2, IL-1β, IL-2, IL-2 가용성 수용체, IL-6, IL-6 가용성 수용체, IL-8, IL-10를 각각 측정하였다. 방법 : 진단 및 치료를 위한 수기 중 채취된 관절 활액에서 각각의 사이토카인 및 그 수용체의 농도를 효소면역측정법으로 측정하였으 Background : The assay of cytokines and their soluble receptors in the synovial fluid of inflammatory arthropathy may be useful in studying pathogenetic and immunoregulatory mechanisms of different arthritis. The aim of this study is to investigate cytoki
류마티스 섬유모세포양 활막세포에서 저산소증 및 사이토카인에 의한 Aggrecanase-1과 Aggrecanase-2 발현 조절
김형진 ( Hyung Jin Kim ),배은경 ( Eun Kyung Bae ),김진희 ( Jin Hee Kim ),채지영 ( Ji Young Chai ),전찬홍 ( Chan Hong Jeon ),차훈석 ( Hoon Suk Cha ),안광성 ( Kwang Sung Ahn ),고은미 ( Eun Mi Koh ) 대한내과학회 2006 대한내과학회지 Vol.71 No.2
목적: 류마티스 관절염 FLS에서 저산소증에 의한 aggrecanase-1, -2 발현의 변화를 알아보고, 각종 사이토카인이 aggrecanase의 발현에 미치는 영향을 살펴 보고자 하였다. 방법: Aggrecanase-1, -2의 mRNA 발현을 관찰하기 위하여 hypoxic chamber에서 FLS를 24시간 동안 배양시킨 세포로부터 분리한 RNA로 cDNA를 합성하고, Real Time PCR을 시행하여 그 결과를 분석하였다. 또한 FLS에 IL-1β, IL-6, IL-8, EGF, TNF-α, TGF-β를 각각 처리하고 24시간 동안 배양하였다. 배양 후 RNA를 분리하여 합성한 cDNA로 real-time PCR을 시행하여 그 결과를 분석하였다. 결과: 저산소 상태에서 aggrecanse-1 mRNA 발현은 정상 산소 상태와 비교하여 8시간 이후부터 2배 이상 증가하였다. Aggrecanase-2 mRNA 발현은 30분 후부터 증가하기 시작하여 1시간째에 이르러 약 2배까지 증가하였으나 그 이후부터는 감소하는 경향을 보였다. Aggrecanase-1 mRNA 발현은 IL-1β에 의해 1.29±0.41배, IL-6에 의해 2.1±0.13배, EGF에 의해 2.65±1.49배, TNF-α에 의해 1.62±0.45배 그리고 TGF-β에 의해 5.0±1.79배 증가하였다. 그러나 IL-8은 aggrecanase-1 유전자 발현을 의미있게 증가시키지 못하였다. Aggrecanase-2 mRNA 발현은 IL-6에 의해 2.28±1.21배 증가하였고, 그 외 TGF-β에 의해 1.88±0.75배, EGF에 의해 1.96± 0.62배 증가한 소견을 보였다. IL-1β와 IL-8은 aggrecanase-2 유전자 발현의 증가에 의미 있는 영향을 미치지 못하였으며 TNF-α는 오히려 발현을 감소시킨 것으로 나타났다. 결론: 류마티스 관절염에서 aggrecanase 발현이 증 가되어 관절, 특히 연골 파괴를 촉진하는데, 그 기전으로 저산소 환경에서 FLS로부터 aggrecanase 생산이 증가됨으로써 관절 파괴에 관여할 것으로 생각된다. Background: While aggrecanases (aggrecanase-1 and aggrecanase-2) are substantially responsible for cartilage aggrecan breakdown in rheumatoid arthritis (RA), not much information is available on the regulation or expression of the two key aggrecanases in rheumatoid fibroblast-like synoviocytes (FLS). The aim of this study is to determine the effect of hypoxia and several cytokines on the expression of the aggrecanases in rheumatoid FLS. Methods: FLS obtained from RA patients were cultured under hypoxic condition for 24 hours. Quantitative polymerase chain reaction assays for mRNA expression of aggrecanase-1 and aggrecanase-2 were performed on FLS cultured under hypoxia. Additionally, to see the effect of various cytokines, same experiments were conducted after treating FLS with IL-1β, IL-6, EGF, TGF-β and TNF-α, compared with control. Results: Hypoxia significantly increased both aggrecanase-1 and -2 mRNA expression in rheumatoid FLS compared with normoxia. IL-1β, IL-6, EGF, TGF-β and TNF-α upregulated the mRNA expression of aggrecanase-1. Both EGF and TGF-β upregulated the mRNA expression of aggrecanase-2, but TNF-α significantly downregulated the mRNA expression of aggrecanase-2. Conclusions: These results showed upregulation of aggrecanase-1 and -2 by hypoxia and differential regulation of aggrecanase-1 and -2 by various cytokines in rheumatoid FLS. It suggests that hypoxia and cytokines enhance the aggrecanase activity of RA FLS and contribute to joint destruction.(Korean J Med 71:182-188, 2006)