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首页> 外文期刊>Journal of Cellular Physiology >Myeloid-specific GPCR kinase-2 negatively regulates NF-kappaB1p105-ERK pathway and limits endotoxemic shock in mice.
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Myeloid-specific GPCR kinase-2 negatively regulates NF-kappaB1p105-ERK pathway and limits endotoxemic shock in mice.

机译：Myeloid-specific GPCR kinase-2负面调节NF-kappaB1p105-ERK通路和限制endotoxemic休克小鼠。

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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 (GRK2triangle upmye). GRK2triangle upmye 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 GRK2triangle upmye mice showed enhanced inflammatory cytokine levels when stimulated with LPS. Our results further identify TLR4-induced NF-kappaB1p105-ERK pathway to be selectively regulated by GRK2. LPS-induced activation of NF-kappaB1p105-MEK-ERK pathway is significantly enhanced in the GRK2triangle upmye macrophages compared to GRK2fl/fl cells and importantly, inhibition of the p105 and ERK pathways in the GRK2triangle upmye 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.
机译：G-protein-coupled受体激酶2 (GRK2)激酶家族成员最初发现磷酸化和对其的作用G-protein-coupled受体的脱敏。它在髓细胞在高水平表达和它的水平在许多炎症改变障碍包括败血症。骨髓特异性GRK2的生理作用在炎症,我们老鼠轴承GRK2生成删除在骨髓细胞(GRK2triangle upmye)。GRK2triangle upmye老鼠表现出夸张的炎性细胞因子/趋化因子生产,器官损伤对脂多糖的回应(有限合伙人,TLR4配体)与野生型相比同窝出生(GRK2fl / fl)。腹膜巨噬细胞从GRK2triangle upmye老鼠表现出增强的炎性细胞因子水平当与LPS刺激。识别TLR4-induced NF-kappaB1p105-ERK通路选择性由GRK2监管。NF-kappaB1p105-MEK-ERK通路的激活显著增强的GRK2triangle upmye比GRK2fl / fl细胞和巨噬细胞重要的是,抑制ERK和施敏原著通路在GRK2triangle upmye巨噬细胞,限制了增强LPS-induced的生产细胞因子/趋化因子。揭示从没被消极的监管作用在TLR4-induced GRK2 p105-ERK通路以及随之而来的炎症细胞因子/趋化因子生产和内毒素老鼠。

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