Hirata Jun-ichi, Kotani Joji, Aoyama Michiko, Kashiwamura Shin-ichiro, Ueda Haruyasu, Kuroda Yasuhiro, Usami Makoto, Okamura Haruki, Marukawa Seishiro
Department of Emergency and Critical Care Medicine, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan.
Shock. 2008 Dec;30(6):628-33. doi: 10.1097/SHK.0b013e31817c0c69.
Decreased neutrophil apoptosis is associated with persistent inflammation, the severity of which correlates with serum IL-18 levels. IL-18 receptors as well as Toll-like receptors, including Toll-like receptor 4, a receptor for LPS, possess a highly conserved intracellular domain called "Toll-IL-1R domain" and activate overlapping signaling pathways. Here, we show that IL-18 modulates neutrophil apoptosis and compare its mechanism of action with LPS. We found that both IL-18 and LPS decreased neutrophil apoptosis in a similar dose- and time-dependent fashion. However, pretreatment with the phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 increased apoptosis more effectively in IL-18- than in LPS-stimulated cells, whereas the ERK inhibitor PD98059 had the same effect in both. In contrast, the p38 mitogen-activated protein kinase (MAPK) inhibitor SB203580 had no influence on apoptosis at all. Neutrophils constitutively expressed mRNA for IL-18 receptor beta, but little or no receptor alpha, both of which increased during coculture with either IL-18 or LPS in a time- and dose-dependent manner. Of the Bcl-2 family, antiapoptotic A1/Bfl-1 tended to increase on IL-18 and LPS stimulation, but was further increased despite increased apoptosis in the presence of MAPK inhibitors. Thus, human neutrophils can express mRNA for IL-18 receptors alpha and beta, and IL-18, like LPS, inhibits neutrophil apoptosis by activating PI3K and ERK pathways but not p38MAPK. However, PI3K may play more important role(s) in IL-18- than in LPS-induced inhibition of apoptosis. Mitogen-activated protein kinases seem to mediate antiapoptotic signals through factors other than Bcl-2 gene family expression.
中性粒细胞凋亡减少与持续性炎症相关，炎症的严重程度与血清白细胞介素 - 18（IL - 18）水平相关。IL - 18受体以及Toll样受体，包括脂多糖（LPS）的受体Toll样受体4，都拥有一个高度保守的细胞内结构域，称为“Toll - IL - 1R结构域”，并激活重叠的信号通路。在此，我们展示了IL - 18调节中性粒细胞凋亡，并将其作用机制与LPS进行比较。我们发现，IL - 18和LPS均以相似的剂量和时间依赖性方式减少中性粒细胞凋亡。然而，用磷脂酰肌醇3 - 激酶（PI3K）抑制剂LY294002预处理，在IL - 18刺激的细胞中比在LPS刺激的细胞中更有效地增加凋亡，而细胞外信号调节激酶（ERK）抑制剂PD98059对两者具有相同的作用。相反，p38丝裂原活化蛋白激酶（MAPK）抑制剂SB203580对凋亡完全没有影响。中性粒细胞组成性地表达IL - 18受体β的mRNA，但很少或不表达受体α，在与IL - 18或LPS共培养期间，两者均以时间和剂量依赖性方式增加。在Bcl - 2家族中，抗凋亡的A1/Bfl - 1在IL - 18和LPS刺激下倾向于增加，但在存在MAPK抑制剂的情况下，尽管凋亡增加，其仍进一步增加。因此，人类中性粒细胞可以表达IL - 18受体α和β的mRNA，并且IL - 18与LPS一样，通过激活PI3K和ERK通路而非p38MAPK来抑制中性粒细胞凋亡。然而，PI3K在IL - 18诱导的凋亡抑制中可能比在LPS诱导的凋亡抑制中发挥更重要的作用。丝裂原活化蛋白激酶似乎通过Bcl - 2基因家族表达以外的因子介导抗凋亡信号。
