Carbon Monoxide Blocks Lipopolysaccharide-Induced Gene Expression by Interfering with Proximal TLR4 to NF-κB Signal Transduction in Human Monocytes
Carbon Monoxide Blocks Lipopolysaccharide-Induced Gene Expression by Interfering with Proximal TLR4 to NF-κB Signal Transduction in Human Monocytes
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DOI：
10.1371/journal.pone.0008139
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发表时间：
2009-12-02
期刊：
影响因子：
3.7
通讯作者：
Danner, Robert L.
中科院分区：
文献类型：
--
作者：
Chhikara, Maneesha;Wang, Shuibang;Danner, Robert L.
一氧化碳（CO）是一种内源性信使，可抑制炎症，调节细胞凋亡和促进血管重塑。在这里，微阵列被用来全面表征CO（250 ppm）抑制早期（1小时）LPS诱导的炎症在人单核细胞THP-1细胞。CO抑制LPS诱导的101个即刻早期基因中的79个，其中19%（15/79）是转录因子，其余大多数是细胞因子、趋化因子和免疫应答基因。CO对转录和蛋白质产生的原型效应发生较早，但迅速下降。CO激活p38 MAPK、ERK 1/2和Akt，并导致LPS诱导的JNK激活的早期和短暂延迟。然而，这些激酶的选择性抑制剂未能阻断CO对LPS诱导的IL-1 β（一种炎症标志物）的抑制。在CO抑制基因中，发现81%（64/79）的启动子具有推定的NF-κ B结合位点。随后显示CO阻断LPS诱导的人单核细胞中Ik B α的磷酸化和降解，从而抑制NF-κ B信号转导。CO通过重塑TLR 4信号转导中的近端事件如应激激酶反应和早期NF-κ B活化广泛抑制人单核细胞对LPS的初始炎症反应。CO的这些快速但短暂的作用可能在急性肺和血管损伤中具有治疗应用。
Carbon monoxide (CO) is an endogenous messenger that suppresses inflammation, modulates apoptosis and promotes vascular remodeling. Here, microarrays were employed to globally characterize the CO (250 ppm) suppression of early (1 h) LPS-induced inflammation in human monocytic THP-1 cells. CO suppressed 79 of 101 immediate-early genes induced by LPS; 19% (15/79) were transcription factors and most others were cytokines, chemokines and immune response genes. The prototypic effects of CO on transcription and protein production occurred early but decreased rapidly. CO activated p38 MAPK, ERK1/2 and Akt and caused an early and transitory delay in LPS-induced JNK activation. However, selective inhibitors of these kinases failed to block CO suppression of LPS-induced IL-1 beta, an inflammation marker. Of CO-suppressed genes, 81% (64/79) were found to have promoters with putative NF-kappa B binding sites. CO was subsequently shown to block LPS-induced phosphorylation and degradation of IkB alpha in human monocytes, thereby inhibiting NF-kappa B signal transduction. CO broadly suppresses the initial inflammatory response of human monocytes to LPS by reshaping proximal events in TLR4 signal transduction such as stress kinase responses and early NF-kappa B activation. These rapid, but transient effects of CO may have therapeutic applications in acute pulmonary and vascular injury.