Myeloid-specific GPCR kinase-2 negatively regulates NF-κB1p105-ERK pathway and limits endotoxemic shock in mice.
Myeloid-specific GPCR kinase-2 negatively regulates NF-κB1p105-ERK pathway and limits endotoxemic shock in mice.
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DOI：
10.1002/jcp.22384
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发表时间：
2011-03
影响因子：
5.6
通讯作者：
Parameswaran, Narayanan
中科院分区：
文献类型：
--
作者：
Patial, Sonika;Saini, Yogesh;Parvataneni, Sitaram;Appledorn, Daniel M.;Dorn, Gerald W., II;Lapres, John J.;Amalfitano, Andrea;Senagore, Patricia;Parameswaran, Narayanan
G蛋白偶联受体激酶2(GRK2)是最早发现的在G蛋白偶联受体的磷酸化和脱敏过程中起作用的一种蛋白激酶家族成员。它在髓系细胞中高水平表达，在包括脓毒症在内的许多炎症性疾病中水平发生变化。为了解决髓系细胞特异性GRK2在炎症中的生理作用，我们产生了携带髓系细胞GRK2缺失的小鼠(GRK2ΔMYE)。与野生型小鼠(GRK2fl/fl)相比，GRK2TLR4MYE小鼠表现出过度的炎性细胞因子/趋化因子的产生，以及对脂多糖(LPS4)的器官损伤。与此一致的是，GRK2ΔMYE小鼠的腹膜巨噬细胞在内毒素刺激下表现出炎症细胞因子水平的升高。我们的结果进一步证实了TLR4诱导的NFGRKB1p105-κ通路受GRK2选择性调控。与GRK2fl/fl细胞相比，脂多糖诱导的GRK2p105-κ-ERK通路在GRK2-Δ细胞中的激活显著增强，更重要的是，抑制了GRK2-Δ-Mye巨噬细胞中p105和ERK通路，限制了细胞因子/趋化因子的增加。综上所述，我们的研究揭示了GRK2在TLR4诱导的p105-ERK途径以及随后的炎性细胞因子/趋化因子的产生和小鼠内毒素血症中的先前未被描述的负调控作用。
G-protein coupled receptor kinase 2 (GRK2) is a member of a kinase family originally discovered for its role in the phosphorylation and desensitization of G-protein coupled receptors. It is expressed in high levels in myeloid cells and its levels are altered in many inflammatory disorders including sepsis. To address the physiological role of myeloid cell-specific GRK2 in inflammation, we generated mice bearing GRK2 deletion in myeloid cells (GRK2Δmye). GRK2Δmye mice exhibited exaggerated inflammatory cytokine/chemokine production, and organ injury in response to lipopolysaccharide (LPS, a TLR4 ligand) when compared to wild type littermates (GRK2fl/fl). Consistent with this, peritoneal macrophages from GRK2Δmye mice showed enhanced inflammatory cytokine levels when stimulated with LPS. Our results further identify TLR4-induced NFκB1p105-ERK pathway to be selectively regulated by GRK2. LPS-induced activation of NFκB1p105-MEK-ERK pathway is significantly enhanced in the GRK2Δmye macrophages compared to GRK2fl/fl cells and importantly, inhibition of the p105 and ERK pathways in the GRK2Δmye macrophages, limits the enhanced production of LPS-induced cytokines/chemokines. Taken together, our studies reveal previously undescribed negative regulatory role for GRK2 in TLR4-induced p105-ERK pathway as well as in the consequent inflammatory cytokine/chemokine production and endotoxemia in mice.
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影响因子：
8.7
作者：
Beutler B
通讯作者：
Beutler B
DOI：
10.4049/jimmunol.0804343
发表时间：
2009-12-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Frazier WJ;Wang X;Wancket LM;Li XA;Meng X;Nelin LD;Cato AC;Liu Y
通讯作者：
Liu Y
影响因子：
4.8
作者：
Cho, J;Melnick, M;Tsichlis, PN
通讯作者：
Tsichlis, PN
影响因子：
3
作者：
Clausen, BE;Burkhardt, C;Förster, I
通讯作者：
Förster, I
影响因子：
64.8
作者：
Baggiolini, M
通讯作者：
Baggiolini, M