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学科主题: 临床医学
题名:
Characterization of a small molecule inhibitor of tumor necrosis factor-alpha production
作者: Yang Gao-yun2; Xie Zhi-qiang1; Qian Ge3; Cui Wen-ying2; Zhao Jun-yin2; Zhang Jian-zhong4; Lian Shi5
关键词: tumor necrosis factor-alpha ; lipopolysaccharides ; peripheral blood mononuclear cell ; cytokine ; mitogen-activated protein kinase
刊名: CHINESE MEDICAL JOURNAL
发表日期: 2010-10-20
DOI: 10.3760/cma.j.issn.0366-6999.2010.20.025
卷: 123, 期:20, 页:2883-2887
收录类别: SCI
文章类型: Article
WOS标题词: Science & Technology
类目[WOS]: Medicine, General & Internal
研究领域[WOS]: General & Internal Medicine
关键词[WOS]: PROTEIN-KINASE ; TNF ; MACROPHAGES ; THALIDOMIDE ; MECHANISMS ; MONOCYTES ; CYTOKINE
英文摘要:

Background Numerous studies have shown that reducing the level of tumor necrosis factor-alpha (TNF alpha) through the use of anti-TNF antibodies or soluble TNF receptor is a safe and efficacious treatment to inflammatory diseases such as rheumatoid arthritis. Therefore, novel approaches to achieve this outcome are desired. The aim of this study was to investigate the characterization of a small molecule inhibitor, Y316, which blocks TNF mRNA upregulation and TNF production by lipopolysaccharides (LPS) stimulated monocytes.

Methods Peripheral blood mononuclear cells (PBMC) from healthy volunteers were plated in 24-well plates and stimulated with LPS (1 mu g/ml), phorbol-12-myristate-13-acetate (PMA) (100 ng/ml), zymosan (10 mu g/ml) and Tsst (100 ng/ml). Supernatants were collected after 4-hour culture at 37 degrees C, and quantitative determination of TNF alpha, interleukin-1 beta (IL-1 beta), IL-6, IL-8, IL-10 and IL-2 production in the supernatants was performed by colorimetric enzyme-linked immunosorbent assay (ELISA). Total RNA of PBMC was isolated and cytokine mRNA quantitation was performed by using a RNA level measuring kit (R & D Systems). PBMC were pretreated with Y316 (10 mu mol/L, 1 mu mol/L, 0.1 mu mol/L, 0.01 mu mol/L and 0.001 mu mol/L) or dimethyl sulfoxide at 37 degrees C for 10 minutes, and then stimulated with LPS or PMA, protein concentrations of p44.42, IKB alpha, P38 and Jun NH2-terminal kinase were determined by Western blotting. Cyclic adenosine-3′,5′-monophosphate (cAMP) of PBMC was measured by enzyme immunoassay kit (Amersham Pharmacia Biotech).

Results Y316 blocked TNF production and inhibited the upregulation of TNF mRNA levels in response to LPS, and also prevented the production of IL-1 and IL-6. In contrast, Y316 augmented the production of IL-10 in LPS-stimulated monocytes. Y316 failed to prevent the production of IL-2 and TNF in antigen-stimulated T cells, suggesting that its effects may be cell-type specific. Y316 prevented the phosphorylation and activation of the MAPK, ERK, and therefore appeared to mediate its effects on TNF by acting at an early point in the signaling cascade induced in response to LPS. There was no effect of Y316 on cAMP levels either alone or in the presence of LPS.

Conclusions Y316 appears to be a small molecule inhibiting TNF production, which may act via a novel mechanism. Identification of the target of Y316 may lead to the development of alternative strategies for achieving selective cytokine inhibition. Chin Med J 2010;123(20):2883-2887

语种: 英语
项目资助者: Beijing Friendship Hospital, Capital Medical University
WOS记录号: WOS:000283694200025
Citation statistics:
内容类型: 期刊论文
URI标识: http://ir.bjmu.edu.cn/handle/400002259/59079
Appears in Collections:北京大学第三临床医学院_皮肤科_期刊论文

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作者单位: 1.Peking Univ, Hosp 3, Dept Dermatol, Beijing 100083, Peoples R China
2.Capital Med Univ, Friendship Hosp, Dept Dermatol, Beijing 100050, Peoples R China
3.Henan Prov Peoples Hosp, Dept Dermatol, Zhengzhou 450000, Henan, Peoples R China
4.Peking Univ, Peoples Hosp, Dept Dermatol, Beijing 100044, Peoples R China
5.Capital Med Univ, Xuanwu Hosp, Dept Dermatol, Beijing 100053, Peoples R China

Recommended Citation:
Yang Gao-yun,Xie Zhi-qiang,Qian Ge,et al. Characterization of a small molecule inhibitor of tumor necrosis factor-alpha production[J]. CHINESE MEDICAL JOURNAL,2010,123(20):2883-2887.
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