Identification of candidate genes downstream of TLR4 signaling after ozone exposure in mice: a role for heat-shock protein 70.
Identification of candidate genes downstream of TLR4 signaling after ozone exposure in mice: a role for heat-shock protein 70.
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DOI：
10.1289/ehp.1003326
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发表时间：
2011-08
影响因子：
10.4
通讯作者：
Kleeberger SR
中科院分区：
文献类型：
--
作者：
Bauer AK;Rondini EA;Hummel KA;Degraff LM;Walker C;Jedlicka AE;Kleeberger SR
背景资料：Toll样受体4（TLR 4）参与臭氧（O3）诱导的肺通透性增高和炎症，尽管下游信号传导事件尚不清楚。目的：我们研究的目的是确定TLR 4调节O3诱导的肺反应的机制，并使用转录组学来确定潜在的TLR 4效应分子。研究方法：C3H/HeJ（HeJ; Tlr 4突变）和C3 H/HeOuJ（OuJ; Tlr 4正常）小鼠连续暴露于0.3 ppm O3或过滤空气6，24，48，或72 hr. We评估炎症使用支气管肺泡灌洗和分子分析mRNA微阵列，定量RT-PCR（实时聚合酶链反应），免疫印迹，免疫染色，ELISA（酶联免疫吸附测定）。B6-Hspa 1a/Hspa 1btm 1Dix/NIEHS（Hsp 70-/-）和C57 BL/6（B6; Hsp 70 +/+野生型对照）小鼠用于候选基因验证研究。结果如下：O3诱导的TLR 4信号通路在OuJ小鼠中通过髓样分化蛋白88（MyD 88）依赖性和非依赖性途径发生，并且涉及多个下游途径。来自空气和O3暴露的HeJ和OuJ小鼠的肺的全基因组转录物分析鉴定了与O3暴露的HeJ小鼠或两种品系的空气暴露对照相比，O3暴露的OuJ小鼠中显著上调的基因簇;该簇包括热休克蛋白的基因（例如，Hsp1b、Hsp70）。此外，与Hsp 70 +/+小鼠相比，Hsp 1a/Hspa 1btm 1Dix（Hsp 70-/-）小鼠中O3诱导的炎症、MyD 88上调、细胞外信号相关激酶1/2（ERK 1/2）和激活蛋白1（AP-1）活化以及角质形成细胞衍生的趋化因子（KC）蛋白含量显著降低（p < 0.05）。
结论：这些研究表明，热休克蛋白70是TLR 4下游的效应分子，并参与调节O3诱导的肺部炎症，触发类似的途径TLR 4。这些新的发现可能对环境暴露引起的炎症性疾病具有治疗和预防意义。
Background: Toll-like receptor 4 (TLR4) is involved in ozone (O3)-induced pulmonary hyperpermeability and inflammation, although the downstream signaling events are unknown. Objectives: The aims of our study were to determine the mechanism through which TLR4 modulates O3-induced pulmonary responses and to use transcriptomics to determine potential TLR4 effector molecules. Methods: C3H/HeJ (HeJ; Tlr4 mutant) and C3H/HeOuJ (OuJ; Tlr4 normal) mice were exposed continuously to 0.3 ppm O3 or filtered air for 6, 24, 48, or 72 hr. We assessed inflammation using bronchoalveolar lavage and molecular analysis by mRNA microarray, quantitative RT-PCR (real-time polymerase chain reaction), immunoblots, immunostaining, and ELISAs (enzyme-linked immunosorbent assays). B6-Hspa1a/Hspa1btm1Dix/NIEHS (Hsp70–/–) and C57BL/6 (B6; Hsp70+/+ wild-type control) mice were used for candidate gene validation studies. Results: O3-induced TLR4 signaling occurred through myeloid differentiation protein 88 (MyD88)-dependent and -independent pathways in OuJ mice and involved multiple downstream pathways. Genomewide transcript analyses of lungs from air- and O3-exposed HeJ and OuJ mice identified a cluster of genes that were significantly up-regulated in O3-exposed OuJ mice compared with O3-exposed HeJ mice or air-exposed controls of both strains; this cluster included genes for heat-shock proteins (e.g., Hspa1b, Hsp70). Moreover, O3-induced inflammation, MyD88
up-regulation, extracellular-signal–related kinase-1/2 (ERK1/2) and activator protein-1 (AP-1) activation, and kerotinocyte-derived chemokine (KC) protein content were significantly reduced in Hspa1a/Hspa1btm1Dix (Hsp70–/–) compared with Hsp70+/+ mice (p < 0.05). Conclusions: These studies suggest that HSP70 is an effector molecule downstream of TLR4 and is involved in the regulation of O3-induced lung inflammation by triggering similar pathways to TLR4. These novel findings may have therapeutic and preventive implications for inflammatory diseases resulting from environmental exposures.
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DOI：
10.1164/rccm.200509-1527oc
发表时间：
2007-04-15
影响因子：
24.7
作者：
Cho, Hye-Youn;Morgan, Daniel L.;Kleeberger, Steven R.
通讯作者：
Kleeberger, Steven R.
DOI：
10.1093/jnci/dji403
发表时间：
2005-12-07
期刊：
JOURNAL OF THE NATIONAL CANCER INSTITUTE
影响因子：
--
作者：
Bauer, AK;Dixon, D;Kleeberger, SR
通讯作者：
Kleeberger, SR
影响因子：
15.9
作者：
Dahl, Morten;Bauer, Alison K.;Kobzik, Lester
通讯作者：
Kobzik, Lester
影响因子：
4.4
作者：
Chase, Margaret A.;Wheeler, Derek S.;Page, Kristen
通讯作者：
Page, Kristen
影响因子：
5.8
作者：
Chanteux H;Guisset AC;Pilette C;Sibille Y
通讯作者：
Sibille Y