GADD34 suppresses lipopolysaccharide-induced sepsis and tissue injury through the regulation of macrophage activation.
GADD34 suppresses lipopolysaccharide-induced sepsis and tissue injury through the regulation of macrophage activation.
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DOI：
10.1038/cddis.2016.116
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发表时间：
2016-05-12
影响因子：
9
通讯作者：
Isobe KI
中科院分区：
文献类型：
--
作者：
Ito S;Tanaka Y;Oshino R;Okado S;Hori M;Isobe KI
生长停滞和DNA损伤诱导蛋白34（GADD 34）是由多种细胞应激，如DNA损伤，内质网应激和氨基酸剥夺诱导的。虽然GADD 34的主要作用是调节ER应激反应和细胞凋亡，但最近的研究表明GADD 34与先天免疫反应有关。在这份报告中，我们研究了GADD 34在细菌感染的炎症反应中的作用。为了探索GADD 34对体内全身性炎症的影响，我们采用脂多糖（LPS）诱导的鼠脓毒症模型，并评估在存在或不存在GADD 34的情况下的致死率、血清细胞因子水平和组织损伤。我们发现GADD 34缺陷增加LPS诱导的脓毒症的致死率和血清细胞因子水平。此外，GADD 34缺陷增强了LPS诱导的急性肝损伤中的组织破坏、细胞死亡和促炎细胞因子表达。LPS刺激后促炎细胞因子的产生受Toll样受体4（TLR 4）介导的NF-κB信号通路的调节。体外实验表明，GADD 34通过IKKβ的去磷酸化抑制巨噬细胞产生促炎细胞因子。总之，GADD 34通过抑制巨噬细胞活化来减轻LPS诱导的脓毒症和急性组织损伤。靶向GADD 34的这种抗炎作用可能是开发调节炎症性疾病的治疗剂的有希望的领域。
Growth arrest and DNA damage inducible protein 34 (GADD34) is induced by various cellular stresses, such as DNA damage, endoplasmic reticulum stress, and amino-acid deprivation. Although the major roles of GADD34 are regulating ER stress responses and apoptosis, a recent study suggested that GADD34 is linked to innate immune responses. In this report, we investigated the roles of GADD34 in inflammatory responses against bacterial infection. To explore the effects of GADD34 on systemic inflammation in vivo, we employed a lipopolysaccharide (LPS)-induced murine sepsis model and assessed the lethality, serum cytokine levels, and tissue injury in the presence or absence of GADD34. We found that GADD34 deficiency increased the lethality and serum cytokine levels in LPS-induced sepsis. Moreover, GADD34 deficiency enhanced tissue destruction, cell death, and pro-inflammatory cytokine expression in LPS-induced acute liver injury. Pro-inflammatory cytokine production after LPS stimulation is regulated by the Toll-like receptor 4 (TLR4)-mediated NF-κB signaling pathway. In vitro experiments revealed that GADD34 suppressed pro-inflammatory cytokine production by macrophages through dephosphorylation of IKKβ. In conclusion, GADD34 attenuates LPS-induced sepsis and acute tissue injury through suppressing macrophage activation. Targeting this anti-inflammatory role of GADD34 may be a promising area for the development of therapeutic agents to regulate inflammatory disorders.