Curriculum in Toxicology, University of North Carolina - Chapel Hill, Chapel Hill, NC, 27599, USA.
Environmental Public Health Division, National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, NC, 27711, USA.
Sci Rep. 2018 Jun 20;8(1):9398. doi: 10.1038/s41598-018-27662-0.
Inter-individual variability is observed in all biological responses; however this variability is difficult to model and its underlying mechanisms are often poorly understood. This issue currently impedes understanding the health effects of the air pollutant ozone. Ozone produces pulmonary inflammation that is highly variable between individuals; but reproducible within a single individual, indicating undefined susceptibility factors. Studying inter-individual variability is difficult with common experimental models, thus we used primary human bronchial epithelial cells (phBECs) collected from many different donors. These cells were cultured, exposed to ozone, and the gene expression of the pro-inflammatory cytokine IL-8 was measured. Similar to in vivo observations, we found that ozone-mediated IL-8 expression was variable between donors, but reproducible within a given donor. Recent evidence suggests that the MAP kinases ERK1/2 and p38 mediate ozone-induced IL-8 transcription, thus we hypothesized that differences in their activation may control IL-8 inter-individual variability. We observed a significant correlation between ERK1/2 phosphorylation and IL-8 expression, suggesting that ERK1/2 modulates the ozone-mediated IL-8 response; however, we found that simultaneous inhibition of both kinases was required to achieve the greatest IL-8 inhibition. We proposed a "dimmer switch" model to explain how the coordinate activity of these kinases regulate differential IL-8 induction.
个体间变异性在所有生物反应中都存在；然而，这种变异性难以建模，其潜在机制通常也难以理解。这个问题目前阻碍了我们对空气污染物臭氧的健康影响的理解。臭氧会引起肺部炎症，在个体之间差异很大；但在单个个体中是可重复的，这表明存在尚未明确的易感性因素。使用常见的实验模型研究个体间变异性是困难的，因此我们使用了从许多不同供体收集的原代人支气管上皮细胞（phBEC）。这些细胞经过培养、暴露于臭氧后，测量促炎细胞因子 IL-8 的基因表达。与体内观察结果相似，我们发现臭氧介导的 IL-8 表达在供体之间存在差异，但在给定供体中是可重复的。最近的证据表明，MAP 激酶 ERK1/2 和 p38 介导臭氧诱导的 IL-8 转录，因此我们假设它们的激活差异可能控制 IL-8 的个体间变异性。我们观察到 ERK1/2 磷酸化与 IL-8 表达之间存在显著相关性，表明 ERK1/2 调节臭氧介导的 IL-8 反应；然而，我们发现同时抑制这两种激酶是实现最大 IL-8 抑制所必需的。我们提出了一个“调光开关”模型来解释这些激酶的协调活性如何调节差异的 IL-8 诱导。
