PMID- 30291869 OWN - NLM STAT- MEDLINE DCOM- 20200226 LR - 20200226 IS - 1873-3913 (Electronic) IS - 0898-6568 (Linking) VI - 53 DP - 2019 Jan TI - Amphiregulin potentiates airway inflammation and mucus hypersecretion induced by urban particulate matter via the EGFR-PI3Kalpha-AKT/ERK pathway. PG - 122-131 LID - S0898-6568(18)30251-1 [pii] LID - 10.1016/j.cellsig.2018.10.002 [doi] AB - Ambient particulate matter (PM) promotes the development and exacerbation of chronic respiratory diseases, including chronic obstructive pulmonary disease (COPD) and asthma, by increasing inflammation and mucus hypersecretion. However, the biological mechanisms underlying PM-induced airway inflammation and mucus hypersecretion remain unclear. Amphiregulin (AREG) is an important ligand for epidermal growth factor receptor (EGFR) and participates in the regulation of several biological functions. Here, the PM-exposed human bronchial epithelial cell (HBEC) model was used to define the role of AREG in PM-induced inflammation and mucus hypersecretion and its related signaling pathways. The expression of AREG was significantly increased in a dose-dependent manner in HBECs subjected to PM exposure. Moreover, PM could induce inflammation and mucus hypersecretion by upregulating the expression of IL-1alpha, IL-1beta, and Muc-5ac in HBECs. The EGFR, AKT, and ERK signaling pathways were also activated in a time- and dose-dependent manner. The AREG siRNA markedly attenuated PM-induced inflammation and mucus hypersecretion, and activation of the EGFR-AKT/ERK pathway. Exogenous AREG significantly increased the expression of IL-1alpha, IL-1beta, and Muc-5ac, and induced activation of the EGFR-AKT/ERK pathway in HBECs. Further, under PM exposure, exogenous AREG significantly potentiated PM-induced inflammation and mucus hypersecretion, and activation of the EGFR-AKT/ERK pathway. Tumor-necrosis factor-alpha converting enzyme (TACE) and EGFR specific inhibitor pretreatment showed that AREG was secreted by TACE-mediated cleavage to regulate PM-induced inflammation and mucus hypersecretion by binding to the EGFR. Moreover, according to the inhibitory effect of specific inhibitors of the class I PI3K isoforms, AKT and ERK, PM-induced inflammation and mucus hypersecretion was regulated by PI3Kalpha activation and its downstream AKT and ERK pathways. This study strongly suggests the adverse effect of AREG in PM-induced inflammation and mucus hypersecretion via the EGFR-PI3Kalpha-AKT/ERK pathway. These findings contribute to a better understanding of the biological mechanisms underlying exacerbation of chronic respiratory diseases induced by PM exposure. CI - Copyright (c) 2018 Elsevier Inc. All rights reserved. FAU - Wang, Jian AU - Wang J AD - Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, N0.180 Fenglin Road, Shanghai 200030, China. FAU - Zhu, Mengchan AU - Zhu M AD - Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, N0.180 Fenglin Road, Shanghai 200030, China. FAU - Wang, Linlin AU - Wang L AD - Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, N0.180 Fenglin Road, Shanghai 200030, China. FAU - Chen, Cuicui AU - Chen C AD - Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, N0.180 Fenglin Road, Shanghai 200030, China. FAU - Song, Yuanlin AU - Song Y AD - Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, N0.180 Fenglin Road, Shanghai 200030, China. Electronic address: ylsong70@163.com. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20181003 PL - England TA - Cell Signal JT - Cellular signalling JID - 8904683 RN - 0 (AREG protein, human) RN - 0 (Amphiregulin) RN - 0 (Particulate Matter) RN - EC 2.7.10.1 (ErbB Receptors) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) SB - IM MH - Amphiregulin/*immunology MH - Cell Line MH - ErbB Receptors/immunology MH - Humans MH - MAP Kinase Signaling System MH - Particulate Matter/*adverse effects MH - Phosphatidylinositol 3-Kinases/immunology MH - Pneumonia/*etiology/immunology MH - Proto-Oncogene Proteins c-akt/immunology MH - Respiratory Mucosa/*immunology MH - *Signal Transduction OTO - NOTNLM OT - Amphiregulin OT - Epidermal growth factor receptor OT - Inflammation OT - Mucus hypersecretion OT - Particulate matter EDAT- 2018/10/07 06:00 MHDA- 2020/02/27 06:00 CRDT- 2018/10/07 06:00 PHST- 2018/06/19 00:00 [received] PHST- 2018/10/02 00:00 [revised] PHST- 2018/10/02 00:00 [accepted] PHST- 2018/10/07 06:00 [pubmed] PHST- 2020/02/27 06:00 [medline] PHST- 2018/10/07 06:00 [entrez] AID - S0898-6568(18)30251-1 [pii] AID - 10.1016/j.cellsig.2018.10.002 [doi] PST - ppublish SO - Cell Signal. 2019 Jan;53:122-131. doi: 10.1016/j.cellsig.2018.10.002. Epub 2018 Oct 3.