Effects of ceramide kinase knockout on lipopolysaccharide-treated sepsis-model mice: Changes in serum cytokine/chemokine levels and increased lethality
Effects of ceramide kinase knockout on lipopolysaccharide-treated sepsis-model mice: Changes in serum cytokine/chemokine levels and increased lethality
复制标题
神经酰胺激酶敲除对脂多糖治疗的脓毒症模型小鼠的影响：血清细胞因子/趋化因子水平的变化和致死率的增加
DOI：
10.1016/j.jphs.2022.05.006
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发表时间：
2022
期刊：
影响因子：
3.5
通讯作者：
Murayama T
中科院分区：
文献类型：
--
作者：
Tanaka A;Honda T;Yasue M;Yamazaki R;Hatakeyama H;Hisaka A;Mashimo M;Kohama T;Nakamura H;Murayama T
神经酰胺是鞘脂代谢的中心分子，通过神经酰胺激酶（CerK）磷酸化为神经酰胺-1-磷酸（C1 P）。CerK/C1 P通路调节许多细胞功能，但其在体内免疫/炎症相关（IIR）疾病中的作用尚不清楚。脓毒症是一种急性全身性炎症性疾病，伴有多器官损伤/功能障碍。在本研究中，我们研究了CerK基因敲除对脂多糖（LPS）处理的脓毒症模型小鼠脓毒症相关事件的发生/进展的影响。在CerK基因敲除小鼠中，与野生型（WT）小鼠相比，静脉注射LPS后48 h的致死率显著增加。CerK敲除增加的致死率在腹腔注射LPS处理的小鼠中重现。测定了包括细胞因子和趋化因子在内的23种IIR分子血清水平的变化。在WT小鼠中，静脉注射LPS后4和/或20 h，这些分子的水平增加。尽管IIR分子的基础水平未受影响，但LPS诱导的白细胞介素-17（IL-17）、C-C基序趋化因子配体（CCL-2和CCL-11）和肿瘤坏死因子-α的增加显著上调，而CerK敲除则略微下调IL-2水平。CerK/C1 P途径介导的调节IIR分子和LPS处理小鼠的致死率增加的推定机制进行了讨论。
Ceramide, a central molecule of sphingolipid metabolism, is phosphorylated to ceramide-1-phosphate (C1P) by ceramide kinase (CerK). The CerK/C1P pathway regulates many cellular functions, but its roles in immune/inflammation-related (IIR) diseasesin vivoare not well known. Sepsis is an acute systemic inflammatory disease accompanied by damage/dysfunction in multiple organs. In the present study, we investigated the effects of CerK knockout on the onset/progression of sepsis-related events in lipopolysaccharide (LPS)-treated sepsis-model mice. In CerK-null mice, the lethality at 48 h after i.v. injection of LPS was significantly increased compared with that in wild-type (WT) mice. The increased lethality by CerK knockout was reproduced in mice treated with i.p. injections of LPS. Changes in serum levels of 23 IIR molecules, including cytokines and chemokines, were measured. In WT mice, levels of these molecules increased 4 and/or 20 h after i.v. injection of LPS. Although the basal levels of IIR molecules were not affected, LPS-induced increases in interleukin-17 (IL-17), C-C motif chemokine ligands (CCL-2 and CCL-11), and tumor necrosis factor-α were significantly up-regulated, whereas IL-2 levels were slightly down-regulated by CerK knockout. Putative mechanisms for the CerK/C1P pathway-mediated regulation of IIR molecules and increased lethality in LPS-treated mice are discussed.