iNOS在LPS誘發TNF-α的角色探討; The requirement of inducible nitric oxide synthase for LPS-mediated tumor necrosis factor alpha secretion

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Title:	iNOS在LPS誘發TNF-α的角色探討;The requirement of inducible nitric oxide synthase for LPS-mediated tumor necrosis factor alpha secretion
Authors:	陳冠妤;Kuan-Yu Chen
Contributors:	中國醫藥大學：醫學研究所
Keywords:	脂多醣體;一氧化氮;腫瘤壞死因子;LPS;TNF-α;iNOS
Date:	2008-07-11
Issue Date:	2009-08-13 14:50:18 (UTC+8)
Abstract:	當病原菌入侵動物體時，會誘導巨噬細胞活化，而inducible nitric oxide synthase (iNOS) 和tumor necrosis factor alpha (TNF-α) 為重要產物。以1400W (為iNOS抑制劑) 及ODQ (為sGC抑制劑) 前處理巨噬細胞，可以同步抑制LPS所產生的TNF-α 。另外以SNAP (NO donor) 及 8-br-cGMP (cGMP類似物) 處理RAW264.7巨噬細胞，皆可增加TNF-α 釋放。與正常巨噬細胞相較，iNOS-null macrophages因LPS刺激所釋出的TNF-α 大幅減少。但SNAP及8-br-cGMP可恢復iNOS-/-巨噬細胞TNF-α 的釋出。有趣的是以PD98059 (MEK抑制劑) 可以有效抑制抑制TNF-α 的產生，而且1400W 及ODQ 皆能有效抑制 LPS-induced TNF-α expression。這些結果意味著NO/cGMP pathway 參與 LPS-induced ERK activation。的確，以LPS處理iNOS-/-巨噬細胞，並不能活化ERK。但是當我們分別處理SNAP或8-br-cGMP，則不論是iNOS-null macrophages或正常的巨噬細胞其ERK活性皆有顯著增加，由上述結果，我們認為LPS刺激後的巨噬細胞會因 NF-κΒ 的活化而產生iNOS。iNOS的釋出NO會啟動下游的訊息傳遞活化了ERK，增加了tnfα 基因的轉錄及TNF-α 的釋出。 Concomitant induction of inducible nitric oxide synthase (iNOS) and generation of TNF-α in LPS-stimulated macrophages raised the possibility that iNOS was involved in TNF-α expression. Consistently, pharmacological blockade or knockout of iNOS reduced LPS-mediated TNF-α secretion. Interestingly, SNAP (a NO donor) or 8-br-cGMP (a cGMP analogue) provoked the production of TNF-α in both wild type and iNOS null macrophages. Previous reports have indicated the participation of MEK and ERK in increasing the transcription of tnfα 　gene. Consistently, LPS-, SNAP-, and 8-br-cGMP-mediated activation of ERK as well as induction of TNF-α were greatly suppressed in macrophages treated with PD98059 (the MEK inhibitor). The strong association between ERK activation and TNF-α secretion in macrophages devoid of iNOS exposed to LPS, SNAP and 8-br-cGMP indicated that via activation of ERK, iNOS was required for LPS-elicited TNF-α generation.
Appears in Collections:	[Graduate Institute of Medical Science] Theses & dissertations

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