Hoogendijk Arie J, Garcia-Laorden M Isabel, van Vught Lonneke A, Wiewel Maryse A, Belkasim-Bohoudi Hakima, Duitman JanWillem, Horn Janneke, Schultz Marcus J, Scicluna Brendon P, van 't Veer Cornelis, de Vos Alex F, van der Poll Tom
1Center for Experimental and Molecular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. 2Center for Infection and Immunity Amsterdam, Amsterdam, The Netherlands. 3Department of Intensive Care, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. 4Laboratory of Experimental Intensive Care and Anesthesiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. 5Division of Infectious Diseases, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
Crit Care Med. 2017 May;45(5):e524-e531. doi: 10.1097/CCM.0000000000002294.
Sepsis is a complex clinical condition associated with high morbidity and mortality. A distinctive feature of sepsis is the reduced capacity of leukocytes to release proinflammatory cytokines in response to ex vivo stimulation. Cellular signaling events leading to immunosuppression in sepsis are not well defined. We investigated cell-specific signaling events underlying the immunosuppressed phenotype in sepsis.
Ex vivo study.
ICU of an academic hospital.
Nineteen patients with sepsis and 19 age-matched healthy controls.
None.
The phosphorylation state of p38 mitogen activated protein kinase and nuclear factor kappa-light-chain-enhancer of activated B cells were determined in ex vivo stimulated CD4 T cells, CD8 T cells, B cells, monocytes, and neutrophils. Messenger RNA expression levels of p38 mitogen activated protein kinase and nuclear factor kappa-light-chain-enhancer of activated B cells and negative regulators tumor necrosis factor-α-induced protein 3 (A20) and mitogen activated protein kinase phosphatase-1 were determined in neutrophils and peripheral blood mononuclear cells. Upon ex vivo stimulation, monocytes of sepsis patients were less capable in phosphorylating nuclear factor kappa-light-chain-enhancer of activated B cells. Sepsis was also associated with reduced phosphorylation of nuclear factor kappa-light-chain-enhancer of activated B cells in stimulated B cells, CD4 and CD8 T cells. Messenger RNA expression levels of nuclear factor kappa-light-chain-enhancer of activated B cells and A20 were diminished in peripheral blood mononuclear cells of sepsis patients, whereas p38 mitogen activated protein kinase messenger RNA was up-regulated. In neutrophils of sepsis patients, mitogen activated protein kinase phosphatase-1 messenger RNA levels were down-regulated.
Sepsis-induced immunosuppression associates with a defect in the capacity to phosphorylate nuclear factor kappa-light-chain-enhancer of activated B cells in lymphoid cells and monocytes.
脓毒症是一种复杂的临床病症，具有高发病率和死亡率。脓毒症的一个显著特征是白细胞在体外刺激下释放促炎细胞因子的能力降低。导致脓毒症免疫抑制的细胞信号转导事件尚未完全明确。我们研究了脓毒症免疫抑制表型背后的细胞特异性信号转导事件。
体外研究。
一家学术医院的重症监护病房。
19例脓毒症患者和19例年龄匹配的健康对照者。
无。
在体外刺激的CD4 T细胞、CD8 T细胞、B细胞、单核细胞和中性粒细胞中测定p38丝裂原活化蛋白激酶和活化B细胞核因子κB的磷酸化状态。在中性粒细胞和外周血单核细胞中测定p38丝裂原活化蛋白激酶、活化B细胞核因子κB以及负调节因子肿瘤坏死因子-α诱导蛋白3（A20）和丝裂原活化蛋白激酶磷酸酶-1的信使RNA表达水平。体外刺激后，脓毒症患者的单核细胞磷酸化活化B细胞核因子κB的能力较低。脓毒症还与刺激的B细胞、CD4和CD8 T细胞中活化B细胞核因子κB的磷酸化减少有关。脓毒症患者外周血单核细胞中活化B细胞核因子κB和A20的信使RNA表达水平降低，而p38丝裂原活化蛋白激酶信使RNA上调。在脓毒症患者的中性粒细胞中，丝裂原活化蛋白激酶磷酸酶-1信使RNA水平下调。
脓毒症诱导的免疫抑制与淋巴细胞和单核细胞中磷酸化活化B细胞核因子κB的能力缺陷有关。
