[논문]LPS로 인한 RAW 264.7 세포의 염증반응에 미치는 achyranthoside E dimethyl ester의 효과

방수영; 김지희; 문형인; 김영희

doi:10.5352/jls.2013.23.6.736

LPS로 인한 RAW 264.7 세포의 염증반응에 미치는 achyranthoside E dimethyl ester의 효과
Anti-inflammatory Effect of Achyranthoside E Dimethyl Ester in LPS-stimulated RAW 264.7 Cells 원문보기

생명과학회지 = Journal of life science, v.23 no.6 = no.158, 2013년, pp.736 - 742

방수영 (부산대학교 자연과학대학 분자생물학과) , 김지희 (부산대학교 자연과학대학 분자생물학과) , 문형인 (동아대학교 생명자원과학대학 의약생명공학과) , 김영희 (부산대학교 자연과학대학 분자생물학과)

초록
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Achyranthoside E dimethyl ester (AEDE)는 Achyranthes japonica에서 분리한 oleanolic acid glycoside이다. 본 연구에서는 대식세포에서 lipopolysaccharide (LPS)로 인한 nitric oxide (NO)의 생성에 미치는 AEDE의 효과를 관찰하고 그 작용 기전을 연구하였다. AEDE는 NO 생성과 inducible NO synthase (iNOS) 발현을 억제하였으며 세포에 독성을 유도하지 않았다. 또한 AEDE는 heme oxygenase-1 (HO-1)의 발현을 유도하였으며, HO-1 siRNA를 처리했을 때 AEDE가 iNOS의 발현을 억제하지 못하였다. AEDE는 HO-1의 발현에 관여하는 전사인자인 nuclear factor E2-related factor 2 (Nrf2)를 핵으로 이동시켰다. 한편 AEDE에 의한 HO-1의 발현은 phosphatidylinositol 3-kinase (PI-3K) 및 extracellular signal regulated kinase (ERK1/2) 억제제에 의해 감소되었으며, AEDE가 Akt와ERK1/2의 인산화를 유도하였다. 이상의 결과를 종합해보면, AEDE는 대식세포에서 PI-3K/Akt/ERK-Nrf2 신호전달과정을 통해 HO-1의 발현을 유도함으로써 NO와 같은 염증매개물질의 생성을 억제한다는 것을 알 수 있다. 이러한 연구결과는 AEDE가 항염증제로 사용될 수 있음을 시사한다.

Abstract ▼ AI-Helper

Achyranthoside E dimethyl ester (AEDE) is an oleanolic acid glycoside from Achyranthes japonica. In this study, we investigated the effects of AEDE on nitric oxide (NO) production and underlying molecular mechanisms in lipopolysaccharide (LPS)-stimulated macrophages. AEDE inhibited LPS-induced NO secretion as well as inducible NO synthase (iNOS) expression, without affecting cell viability. Further study demonstrated that AEDE induced heme oxygenase-1 (HO-1) gene expression. In addition, the inhibitory effects of AEDE on iNOS expression were abrogated by small interfering RNA-mediated knock-down of HO-1. Moreover, AEDE induced nuclear translocation of nuclear factor E2-related factor 2 (Nrf2), a transcription factor that regulates HO-1 expression. AEDE-induced expression of HO-1 was inhibited by inhibitors of phosphatidylinositol 3-kinase (PI-3K) and extracellular signal regulated kinase (ERK1/2). AEDE phosphorylated Akt and ERK1/2 as well. Therefore, these results suggest that AEDE suppresses the production of pro-inflammatory mediator such as NO by inducing HO-1 expression via PI-3K/Akt/ERK-Nrf2 signaling. These findings provide the scientific rationale for anti-inflammatory therapeutic use of AEDE.

주제어

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제안 방법

TATA binding protein (TBP) was used as protein-loading controls for each lane. Quantitative image analysis was performed using image analysis software, ImageJ (http://rsb.info.nih.gov/ij) and data were presented as fold of control.

데이터처리

Statistical significances were compared between each treated group and analyzed by the Student’s t-test.

이론/모형

NO synthesis in cell cultures was measured by a microplate assay method. To measure nitrite, 100 μl aliquots were removed from conditioned medium and incubated with an equal volume of the Griess reagent (1% sulfanilamide/0.
7 cells were incubated with AEDE for 1 h and stimulated with LPS for 20 h. The amount of NO released into culture medium was measured by the method of Griess. Whereas LPS-treated cells produced a large amount of NO, AEDE suppressed NO release into culture supernatant in a dose-dependent manner (Fig.
1 μg/ml) for 20 h. The amount of nitrite released was measured by the method of Griess. (C) Cells were treated as mentioned above and equal cytosolic extracts were analyzed by Western blotting.
The cytotoxicity of AEDE was assessed using the microculture tetrazolium (MTT)-based colorimetric assay. The remaining cells after Griess reaction were used for MTT assay.

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