Transient Receptor Potential Melastatin 2 Is Required for Lipopolysaccharide-Induced Cytokine Production in Human Monocytes
Transient Receptor Potential Melastatin 2 Is Required for Lipopolysaccharide-Induced Cytokine Production in Human Monocytes
复制标题
DOI：
10.4049/jimmunol.0902474
复制
发表时间：
2010-03-01
影响因子：
4.4
通讯作者：
Hauschildt, Sunna
中科院分区：
文献类型：
--
作者：
Wehrhahn, Janine;Kraft, Robert;Hauschildt, Sunna
瞬时受体电位melastatin 2（TRPM 2）是一种钙离子可渗透的非选择性阳离子通道，可被氧化应激刺激并被细胞内ADP-核糖特异性激活。由于TRPM 2在免疫细胞中高度表达，因此已经提出了该通道在炎症过程中的作用。本研究的目的是确定TRPM 2在LPS诱导的人单核细胞细胞因子产生中的功能。用LIPS孵育人原代单核细胞导致TRPM 2 mRNA、蛋白和ADP-核糖诱导的膜电流上调。通过使用短发夹RNA下调THP-1单核细胞中TRPM 2的表达，我们证明了TRPM 2是LPS诱导的IL-6、IL-8、IL-10和TNF-α产生所必需的。LPS的应用导致THP-1细胞内Ca 2+浓度的时间依赖性增加，TRPM 2的下调明显降低。细胞外Ca 2+的缺失强烈降低了TRPM 2表达细胞中TNF-α的产生。因此，TRPM 2介导的Ca 2+内流是LPS诱导单核细胞产生细胞因子的中心机制。TRPM 2作为该LPS依赖性过程中的主要参与者的鉴定使其成为调节单核细胞功能的有希望的工具。免疫学杂志，2010，184：2386-2393。
Transient receptor potential melastatin 2 (TRPM2) is a Ca2+-permeable nonselective cation channel that is stimulated by oxidative stress and specifically activated by intracellular ADP-ribose. Because TRPM2 is highly expressed in immunocytes, a role of this channel in inflammation processes has been proposed. The aim of the current study was to determine the function of TRPM2 in LPS-induced cytokine production of human monocytes. Incubation of human primary monocytes with LIPS resulted in an upregulation of TRPM2 mRNA, protein, and of ADP-ribose-induced membrane currents. By using short hairpin RNA to down-regulate TRPM2 expression in THP-1 monocytes, we demonstrate that TRPM2 is required for the LPS-induced production of IL-6, IL-8, IL-10, and TNF-alpha. Application of LPS led to a time-dependent increase in intracellular Ca2+ concentrations in THP-1 cells that was clearly reduced by downregulation of TRPM2. Omission of extracellular Ca2+ strongly decreased TNF-alpha production in TRPM2-expressing cells. Thus, TRPM2-mediated Ca2+ entry is a central mechanism for LPS-induced cytokine production in monocytic cells. The identification of TRPM2 as a major player in this LPS-dependent process makes it a promising tool in modulating monocyte functions., The Journal of Immunology, 2010, 184: 2386-2393.