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Received March 25, 2009
Accepted July 18, 2009
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수용성 EPCR에 의한 활성화된 단백질 C의 항염증 작용에 관한 연구
Effect of Soluble EPCR on the Anti-Inflammatory Effects by Activated Protein C
대구한의대학교 한방제약공학과, 712-715 경상북도 경산시 유곡동 290번지 1부산대학교 화학공학과, 609-735 부산시 금정구 장전동 산 30
Department of Herbal Pharmaceutical Engineering, Daegu Haany University, 290, Yugok-dong, Gyeongsan-si, Gyeongsangbuk-do 712-715, Korea 1Division of Chemical Engineering, Pusan National University, San 30, Jangjun-dong, Gumjung-gu, Busan 609-735, Korea
moonki@dhu.ac.kr
Korean Chemical Engineering Research, August 2009, 47(4), 501-505(5), NONE Epub 25 August 2009
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Abstract
본 논문에서는 혈관내피세포에서 활성화된 단백질 C(Activated Protein C, APC)의 항염증 작용에서 수용성 EPCR(Soluble Endothelial Protein C Receptor, sEPCR)의 효과를 관찰하였다. sEPCR은 APC가 매개하는 항염증 작용에 있어 내피세포막의 보호효과를 저해하고, 혈관내피세포에 대한 백혈구의 부착저해 효과를 억제하며, 혈관내피세포를 관통하는 백혈구의 이동을 저해하는 효과를 억제한다. 그리고 흥미롭게도 sEPCR은 내피세포에서 TNF-alpha에 의한 세포부착단백질의 발현을 억제하는 APC의 기전을 저해함으로써 APC가 가지는 항염증 효과를 억제한다. 이것은 APC의 Gla 도메인이 내피세포의 수용체인 EPCR에 결합할 수 있는 부위에 sEPCR이 상호작용함으로써 더 이상 APC이 세포막에 존재하는 EPCR과 결합을 못함으로써 APC의 항염증 작용은 억제되는 것을 의미한다. 이 결과는 향후 중증패혈증 및 염증질환을 효과적으로 치료할 수 있는 신약개발에 중요한 단서를 제공할 것이고 내피세포에서 아직 명확하게 밝혀지지 않은 APC의 항염증 작용의 기전을 밝히는 데 좋은 정보를 제공할 것이다.
In this study, we evaluated the effect of soluble EPCR(Soluble Endothelial Protein C Receptor, sEPCR) on the anti-inflammatory activities by activated protein C(APC) in endothelium. We demonstrated that sEPCR inhibited the barrier protective activity, the inhibition of neutrophils adhesion toward endothelial cells and the inhibition of transendothelial migration by APC in endothelial cells. Interestingly, sEPCR also blocked the mechanism by which APC inhibited_x000D_
the expression of cell adhesion molecules(CAM) by TNF-alpha in endothelial cells. These results suggested that the anti-inflammatory activities of APC was inhibited by sEPCR which blocked the binding motifs of Gla domain of APC to membrane bound EPCR. This finding will provide the important evidence in the development of new medicine for the treatment of severe sepsis and inflammatory diseases and good clue for understanding unknown mechanisms by_x000D_
which APC showed the anti-inflammatory activities in endothelium.
Keywords
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Joyce DE, Gelbert L, Ciaccia A, DeHoff B, Grinnell BW, J. Biol. Chem., 264, 11199 (2001)
Riewald M, Petrovan RJ, Donner A, Mueller BM, Ruf W, Science, 296, 1880 (2002)
Mosnier LO, Griffin JH, Biochem. J., 373, 65 (2003)
Cheng T, Liu D, Griffin JH, Fernandez JA, Castellino F, Rosen ED, Fukudome K, Zlokovic BV, Nat. Med., 9, 338 (2003)
Guo H, Liu D, Gelbard H, Cheng T, Insalaco R, Fernandez JA, Griffin JH, Zlokovic BV, Neuron, 41, 563 (2004)
Bae JS, Yang L, Manditody C, Rezaie AR, Blood, 110, 3909 (2007)
Bae JS, Yang L, Manditody C, Rezaie AR, J. Biol. Chem., 282, 9251 (2007)
Bernard GR, Vincent JL, Laterre PF, LaRosa SP, Dhainaut JF, Lopez-Rodriguez A, Steingrub JS, Garber GE, Helterbrand JD, Ely EW, Fisher CJ Jr., N. Engl. J. Med., 344, 699 (2001)
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Esmon ST, Chest, 124, 26S (2003)
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Bae JS, Rezaie AR, Semin, Thrombo. Haemost., 100, 101 (2008)
