Department of Air Pollution and Noise, Division of Environmental Medicine, Norwegian Institute of Public Health, P.O. Box 4404, Nydalen, N-0403 Oslo, Norway; Department of Biology, Faculty of Mathematics and Natural Sciences, University of Oslo, P.O. Box 1066, Blindern, N-0316 Oslo, Norway.
Department of Air Pollution and Noise, Division of Environmental Medicine, Norwegian Institute of Public Health, P.O. Box 4404, Nydalen, N-0403 Oslo, Norway.
Toxicol Lett. 2014 Jul 3;228(1):42-7. doi: 10.1016/j.toxlet.2014.03.021. Epub 2014 Apr 4.
Inflammation is considered central in the pathology of health effects from airborne particulate matter (PM). Preexisting inflammatory disorders, such as asthma, but also pulmonary infections, appear to be a risk factor of adverse health effects from PM exposure. Thus, to assess whether and how preexisting inflammation may sensitize lung cells toward additional proinflammatory effects of PM, human bronchial epithelial cells (BEAS-2B) were primed with the highly proinflammatory Toll-like receptor 3 (TLR3) ligand, Poly I:C, prior to exposure with diesel exhaust particles (DEP). DEP-exposure alone induced increased gene-expression of interleukin-6 (IL-6) and CXCL8 (IL-8) but did not affect expression of CCL5 (RANTES), while TLR3-priming alone induced expression of IL-6, CXCL8 and CCL5. DEP-exposure exacerbated IL-6 and CXCL8 responses in TLR3-primed cells, while TLR3-induced CCL5 was suppressed by DEP. TLR3-priming and DEP-exposure resulted in possible additive effects on p38 phosphorylation and IκB-degradation, while DEP rather suppressed ERK and JNK-activation. However, TLR3-priming elicited a considerable increase in p65-phosphorylation at serine 536 which is known to enhance the transcriptional activity of NF-κB. DEP-exposure was unable to induce p65-phosphorylation. Thus TLR3-priming may affect susceptibility toward DEP by activating both shared and complementing pathways required for optimal expression of proinflammatory genes such as IL-6 and CXCL8. The study underscores that primed "sick" cells may be more susceptible toward effects of particle-exposure and respond both stronger and differently compared to unprimed "healthy" cells.
炎症被认为是空气中颗粒物（PM）对健康影响的病理学核心。先前存在的炎症性疾病，如哮喘，但也包括肺部感染，似乎是 PM 暴露不良健康影响的一个风险因素。因此，为了评估先前存在的炎症是否以及如何使肺细胞对 PM 的额外促炎作用变得敏感，在暴露于柴油机废气颗粒（DEP）之前，用高度促炎的 Toll 样受体 3（TLR3）配体 Poly I:C 对人支气管上皮细胞（BEAS-2B）进行了预处理。DEP 暴露本身诱导白细胞介素 6（IL-6）和 CXCL8（IL-8）的基因表达增加，但不影响 CCL5（RANTES）的表达，而 TLR3 预处理本身诱导 IL-6、CXCL8 和 CCL5 的表达。DEP 暴露加剧了 TLR3 预处理细胞中 IL-6 和 CXCL8 的反应，而 TLR3 诱导的 CCL5 被 DEP 抑制。TLR3 预处理和 DEP 暴露对 p38 磷酸化和 IκB 降解产生可能的相加作用，而 DEP 反而抑制了 ERK 和 JNK 的激活。然而，TLR3 预处理导致 p65 丝氨酸 536 磷酸化显著增加，已知该磷酸化增强 NF-κB 的转录活性。DEP 暴露不能诱导 p65 磷酸化。因此，TLR3 预处理可能通过激活共同和互补的途径来影响对 DEP 的易感性，这些途径对于最佳表达促炎基因如 IL-6 和 CXCL8 是必需的。该研究强调，预处理的“病态”细胞可能对颗粒暴露的影响更敏感，并比未预处理的“健康”细胞反应更强且不同。
