Modulation of macrophage responsiveness to lipopolysaccharide by IRAK-1 manipulation
Modulation of macrophage responsiveness to lipopolysaccharide by IRAK-1 manipulation
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DOI：
10.1097/01.shk.0000111828.07309.26
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发表时间：
2004-02-01
期刊：
影响因子：
3.1
通讯作者：
Maier, RV
中科院分区：
文献类型：
--
作者：
Cuschieri, J;Bulmus, V;Maier, RV
内毒素局部激活巨噬细胞对于根除侵袭性革兰氏阴性菌感染是必不可少的。较低浓度的循环内毒素导致远端部位的免疫细胞活化，从而导致组织损伤。虽然这些潜在的不同事件中涉及的细胞机制是不完整的，但似乎近端激酶IRAK-1起作用。因此，正义和反义IRAK-1寡核苷酸用于确定IRAK-1在THP-1细胞内通过全身（1-100 ng/mL）和局部（1000 ng/mL）浓度的脂多糖（LPS）激活巨噬细胞中的作用。在有义组内，有义组内1-1000 ng/mL的LPS导致ERK-1/2、p38和JNK/SAPK的细胞活化以及NF-κ B和AP-1的核活化。这种激活与促炎细胞因子的产生和细胞扩散有关。与有义组相比，反义组内LPS的全身浓度与细胞内信号传导、细胞因子产生和细胞扩散的显著衰减相关。然而，在反义组内的LPS的局部浓度仅与细胞内信号传导的延迟相关，与有义组相比，对细胞因子产生或细胞扩散没有影响。基于这些结果，IRAK-1似乎对全身而非局部浓度的LPS下的巨噬细胞活化至关重要。这些数据表明，冗余的途径存在，在较高浓度的LPS的功能。因此，IRAK-1似乎是参与感染性休克期间远端部位巨噬细胞活化的中心激酶，但对于局部感染区域的活化不是必需的。
Local activation of the macrophage by endotoxin is essential for the eradication of invasive gram-negative infections. Circulating endotoxin at lower concentrations results in immune cell activation at distant sites leading to tissue injury. Although the cellular mechanisms involved in these potentially dissimilar events are incomplete, it appears that the proximal kinase IRAK-1 plays a role. Thus, sense and antisense IRAK-1 oligonucleotides were used to determine the role IRAK-1 plays in macrophage activation by systemic (1-100 ng/mL) and local (1000 ng/mL) concentration of lipopolysaccharide (LPS) within THP-1 cells. Within the sense group, 1-1000 ng/mL of LPS within the sense group resulted in cellular activation of ERK-1/2, p38, and JNK/SAPK and the nuclear activation of NF-kappaB and AP-1. This activation was associated with proinflammatory cytokine production and cellular spreading. Systemic concentrations of LPS within the antisense group were associated with significant attenuation of intracellular signaling, cytokine production, and cellular spreading compared with the sense group. Local concentrations of LPS within the antisense group, however, were associated only with a delay in intracellular signaling, with no effect on cytokine production or cell spreading compared with the sense group. Based on these results, it appears that IRAK-1 is essential to macrophage activation at systemic, but not local, concentrations of LPS. These data suggest that redundant pathways exist that are functional at higher concentrations of LPS. Therefore, IRAK-1 appears to be the central kinase involved in the activation of the macrophage at distant sites during septic shock but is not necessary for activation in areas of local infection.