Transcriptional Control of Cytokine Release from Monocytes of the Newborn: Effects of Endogenous and Exogenous Interleukin-10 versus Dexamethasone
Transcriptional Control of Cytokine Release from Monocytes of the Newborn: Effects of Endogenous and Exogenous Interleukin-10 versus Dexamethasone
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DOI：
10.1159/000235807
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发表时间：
2010-01-01
期刊：
影响因子：
2.5
通讯作者：
Davidson, Dennis
中科院分区：
文献类型：
--
作者：
Chusid, Lina A.;Pereira-Argenziano, Lucy;Davidson, Dennis
背景：单核细胞在胎儿和新生儿炎症反应综合征中起重要作用。它们也是肺泡巨噬细胞、小胶质细胞和枯否细胞的前体。单核细胞具有促炎（PI）和抗炎（AI）功能。白细胞介素（IL）-10是由单核细胞释放的有效AI细胞因子。目的：我们确定了内源性和外源性IL-10与等摩尔水平的地塞米松（DEX）对PI和AI细胞因子释放的影响，以及转录因子DNA结合活性，内毒素（脂多糖，LPS）刺激的新生儿单核细胞。方法：从脐带血中分离单核细胞，加入培养基中培养。采用ELISA、电泳迁移率变动分析和蛋白质印迹法。结果如下：通过加入IL-10单克隆抗体，LPS刺激的PI细胞因子、肿瘤坏死因子-α（TNF-α、IL-1 β和IL-8）的单核细胞释放在18小时内显著增强。10（-8）M的外源性IL-10抑制PI细胞因子释放89- 97%，而等摩尔水平的DEX没有影响。PI转录因子核因子-κ B（NF-κ B B）和激活蛋白-1（AP-1）以及AI转录因子信号转导子和转录激活子3（STAT 3）的DNA结合活性被诱导超过18 h。10（-8）M的DEX对任何转录因子DNA结合都没有影响，但10（-8）M的外源性IL-10对AP-1 DNA结合产生了60%的抑制，并增强了核STAT 3的磷酸化。结论：在治疗水平的DEX下，与IL-10相比，PI细胞因子的单核细胞释放对DEX不敏感。IL-10或其作用机制可能导致围产期炎症性疾病的新疗法。版权所有（C）2009 S. Karger AG，巴塞尔
Background: Monocytes play an important role in the fetal and neonatal inflammatory response syndrome. They are also the precursors of alveolar macrophages, microglial and Kupffer cells. Monocytes have pro-inflammatory (PI) and anti-inflammatory (AI) functions. Interleukin (IL)-10 is a potent AI cytokine released by monocytes. Objective: We determined the effects of endogenous and exogenous IL-10 versus equimolar levels of dexamethasone (DEX) on PI and AI cytokine release, as well as transcription factor DNA-binding activity, in endotoxin (lipopolysaccharide, LPS)-stimulated monocytes of the newborn. Methods: Monocytes were isolated into culture media from cord blood. ELISAs, electrophoretic mobility shift assays and Western blots were employed. Results: LPS-stimulated monocyte release of PI cytokines, tumor necrosis factor-alpha (TNF-alpha, IL-1 beta and IL-8, over 18 h was significantly augmented by addition of an IL-10 monoclonal antibody. Exogenous IL-10 at 10(-8) M inhibited PI cytokine release by 89-97%, while DEX at an equimolar level had no effect. DNA-binding activities of the PI transcription factors nuclear factor-kappa B (NF-kappa B) and activator protein-1 (AP-1), and the AI transcription factor signal transducer and activator of transcription 3 (STAT3) were induced over 18 h. DEX at 10(-8) M had no effect on any transcription factor DNA binding, but exogenous IL-10 at 10(-8) M produced a 60% inhibition of AP-1 DNA binding and enhanced phosphorylation of nuclear STAT3 for 18 h. Conclusion: At therapeutic levels of DEX, monocyte release of PI cytokine was insensitive to DEX in comparison to IL-10. IL-10 or its mechanism of action could lead to new therapy for inflammatory disorders in the perinatal period. Copyright (C) 2009 S. Karger AG, Basel