G-protein-coupled receptor kinase-5 mediates inflammation but does not regulate cellular infiltration or bacterial load in a polymicrobial sepsis model in mice.
G-protein-coupled receptor kinase-5 mediates inflammation but does not regulate cellular infiltration or bacterial load in a polymicrobial sepsis model in mice.
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DOI：
10.1159/000347002
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发表时间：
2013
影响因子：
5.3
通讯作者：
Parameswaran N
中科院分区：
文献类型：
--
作者：
Packiriswamy N;Lee T;Raghavendra PB;Durairaj H;Wang H;Parameswaran N
在包括脓毒症在内的多种疾病中，NF-κB依赖的信号转导是炎症反应的重要调节因子。G蛋白偶联受体激酶5(GRK5)是一种进化保守的核因子κB途径调节因子。我们推测，GRK5通过核因子κB的调节在脓毒症的发病机制中起重要作用。为了验证这一点，我们使用了一种临床相关的多菌败血症模型，该模型在GRK5基因缺陷的小鼠身上进行。我们对野生型(WT)和GRK5基因敲除(KO)小鼠进行盲肠结扎和穿孔(CLP)诱导的多菌败血症，并评估败血症发病机制中的各种事件。CLP在WT诱导了显著的炎症反应，而在KO小鼠中这种反应明显减弱。为探讨NFκB激活在脓毒症炎症反应中的信号机制和作用，我们检测了两种基因型大鼠肝脏IκBα磷酸化水平和NFκB依赖基因的表达。与WT小鼠相比，GRK5KO小鼠IκBα的磷酸化和基因表达均受到显著抑制。然而，有趣的是，在脓毒症诱导后，GRK5既没有调节免疫细胞的渗透(到主要感染部位)，也没有调节局部/全身细菌负荷。相反，体内GRK5缺乏显着抑制脓毒症诱导的血浆皮质酮水平和随后的胸腺细胞凋亡。与这些结果相关的是，在GRK5 KO小鼠中，在抗生素存在的情况下，CLP诱导的死亡被显著防止。总之，我们的研究表明，GRK5在多菌败血症中是炎症和胸腺细胞凋亡的重要调节因子，并可能是脓毒症中一个潜在的分子靶点。
NFκB-dependent signaling is an important modulator of inflammation in several diseases including sepsis. G-protein coupled receptor kinase-5 (GRK5) is an evolutionarily conserved regulator of NFκB pathway. We hypothesized that GRK5 via NFκB regulation plays an important role in the pathogenesis of sepsis. To test this we utilized a clinically relevant polymicrobial sepsis model in mice that were deficient in GRK5. We subjected wild type (WT) and GRK5 knockout (KO) mice to cecal-ligation and puncture (CLP)-induced polymicrobial sepsis and assessed the various events in sepsis pathogenesis. CLP induced a significant inflammatory response in the WT and this was markedly attenuated in the KO mice. To determine the signaling mechanisms and the role of NFκB activation in sepsis-induced inflammation, we assessed the levels of IκBα phosphorylation and expression of NFκB-dependent genes in the liver in the two genotypes. Both IκBα phosphorylation and gene expression were significantly inhibited in the GRK5 KO compared to the WT mice. Interestingly however, GRK5 did not modulate either immune cell infiltration (to the primary site of infection) or local/systemic bacterial load subsequent to sepsis induction. In contrast GRK5 deficiency significantly inhibited sepsis-induced plasma corticosterone levels and the consequent thymocyte apoptosis in vivo. Associated with these outcomes, CLP-induced mortality was significantly prevented in the GRK5 KO mice in the presence of antibiotics. Together, our studies demonstrate GRK5 as an important regulator of inflammation and thymic apoptosis in polymicrobial sepsis and implicate GRK5 as a potential molecular target in sepsis.
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G蛋白偶联受体激酶5的HIP磷酸化调节趋化因子受体CXCR4的内在化。
影响因子：
2.9
作者：
Barker, Breann L.;Benovic, Jeffrey L.
通讯作者：
Benovic, Jeffrey L.
DOI：
10.1073/pnas.96.25.14541
发表时间：
1999-12-07
影响因子：
11.1
作者：
Hotchkiss, RS;Tinsley, KW;Karl, IE
通讯作者：
Karl, IE
影响因子：
3.1
作者：
AYALA, A;HERDON, CD;CHAUDRY, IH
通讯作者：
CHAUDRY, IH
影响因子：
11.4
作者：
Barthet, Gael;Carrat, Gaelle;Dumuis, Aline
通讯作者：
Dumuis, Aline
影响因子：
3.3
作者：
Nair, A;Bonneau, RH
通讯作者：
Bonneau, RH