Lipopolysaccharide-induced NF-κB activation and cytokine release in human alveolar macrophages is PKC-independent and TK- and PC-PLC-dependent
Lipopolysaccharide-induced NF-κB activation and cytokine release in human alveolar macrophages is PKC-independent and TK- and PC-PLC-dependent
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DOI：
10.1165/ajrcmb.18.3.2972
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发表时间：
1998-03-01
影响因子：
6.4
通讯作者：
Hunninghake, GW
中科院分区：
文献类型：
--
作者：
Carter, AB;Monick, MM;Hunninghake, GW
脓毒症诱导的成人呼吸窘迫综合征(ARDS)的一个重要特征是内毒素(LPS)激活的肺泡巨噬细胞(AM)释放细胞因子(如IL-6、IL-8和肿瘤坏死因子[TNF])。核因子-kappaB在ARDS患者AM中被激活，是许多细胞因子基因转录所必需的。在这些研究中，我们评价了内毒素诱导的细胞因子释放的调节和核因子-kappaB在人AM中的激活。我们发现，肺泡巨噬细胞在内毒素作用下，其核因子-kappaB的激活和IL-6、IL-8、肿瘤坏死因子的释放是蛋白激酶C不依赖的，酪氨酸酶和磷脂酰胆碱特异的磷脂酶C是依赖的。我们还发现，在有血清培养的AM中或在LPS结合蛋白存在的情况下，内毒素诱导的核因子-kappa B的激活被增强，这模拟了ARDS中存在的肺条件。此外，内毒素可激活AM中几种不同的核因子-kappaB复合体，不同形式的核因子-kB与IL-6、IL-8和肿瘤坏死因子启动子序列结合。这些观察表明，ARDS患者肺部存在的生理异常促进了核因子-KB的激活和局部细胞因子的释放。
A critical feature of sepsis-induced adult respiratory distress syndrome (ARDS) is the release of cytokines (such as interleukin [IL]-6, IL-8, and tumor necrosis factor [TNF]) from endotoxin (lipopolysaccharide [LPS])-activated alveolar macrophages (AM). Nuclear factor kappa B (NF-kappa B) is activated in AM from patients with ARDS, and it is essential for the transcription of many cytokine genes, In these studies, we evaluated the regulation of LPS-induced cytokine release and the activation of NF-kappa B in human AM. We found that the activation of NF-kappa B and the release of IL-6, IL-8, and TNF from AM exposed to LPS was protein kinase C-independent and tyrosine kinase-and phosphatidylcholine-specific phospholipase C-dependent. We also found that LPS-induced activation of NF-kappa B was enhanced in AM cultured in serum or in the presence of LPS-binding protein, simulating conditions in the lung that are present in ARDS. In addition, LPS triggered the activation of several different NF-kappa B complexes in AM, and different forms of NF-KB bound to the IL-6, IL-8, and TNF promoter sequences. These observations suggest that physiologic abnormalities present in the lungs of patients with ARDS facilitate the activation of NF-KB and local release of cytokines.