Induction of CCAAT/enhancer-binding protein–homologous protein by cigarette smoke through the superoxide anion-triggered PERK–eIF2α pathway

Tagawa, Yasuhiro; Hiramatsu, Naoki; Kato, Hironori; Sakoh, Takashi; Nakajima, Shotaro; Hayakawa, Kunihiro; Saito, Youhei; Johno, Hisashi; Takahashi, Shuhei; Gu, Liya; Yao, Jian; Kitamura, Masanori

doi:10.1016/j.tox.2011.06.005

Cited by 24 publications

(25 citation statements)

References 36 publications

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“…Now, what is the effect of the phosphorylation of eIF2 after exposure to cigarette smoke. Initial studies showed a correlation of eIF2 with the induction of cellular apoptosis [27,28,29,30,31]. Accordingly, our in vitro results show that inhibition of the phosphorylation of eIF2 using a dominant negative form of eIF2 prevented the T cell apoptosis induced by CSE.…”

Section: Discussionsupporting

confidence: 71%

“…Previous studies have shown that exposure of cells or rats to cigarette smoke induces the phosphorylation of eIF2 [27,28,29,30,31]. Furthermore, a high induction of UPR stress-related proteins, including phospho-eIF2 , was detected in the lung from heavy smokers [12].…”

Section: Discussionmentioning

confidence: 99%

“…Four different kinases, the double-stranded RNA-dependent protein kinase (PKR), the hemin-regulated inhibitor (HRI), the PKR-like endoplasmic reticulum-related kinase (PERK), and the general control non-repressed 2 kinase (GCN2), phosphorylate eIF2 in response to different stress signals [33,15]. Previous studies have suggested the role of PERK in the phosphorylation of eIF2 induced by CSE [29,27,31]. In contrast, our experiments silencing the expression of eIF2 -kinases in CCRF-CEM cells showed neither a retardation in the eIF2 phosphorylation nor a prevention in CSE-induced apoptosis (data not shown), suggesting a potential role of the dephosphorylation of eIF2 as the mechanisms for the high levels of phospho-eIF2 in CSE-treated T cells.…”

Section: Discussionmentioning

confidence: 99%

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Effects of cigarette smoke extract on primary activated T cells

Hernandez

Morrow

Velasco

et al. 2013

Cellular Immunology

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Tobacco smoking predisposes the development of diseases characterized by chronic inflammation and T cell dysfunction. In this study, we aimed to determine the direct effects of cigarette smoke on primary T cells and to identify the corresponding molecular mediators. Activated T cells cultured in the presence of cigarette smoke extract (CSE) displayed a dose-dependent decrease in cell proliferation, which associated with the induction of cellular apoptosis. T cell apoptosis by CSE was independent of caspases and mediated through reactive oxygen and nitrogen species endogenously contained within CSE. Additional results showed that exposure of T cells to CSE induced phosphorylation of the stress mediator eukaryotic-translation-initiation-factor 2 alpha (eIF2 ). Inhibition of the phosphorylation of eIF2 in T cells prevented the cellular apoptosis induced by CSE. Altogether, the results show the direct effects of CSE on T cells, which advance in the understanding of how cigarette smoking promotes chronic inflammation and immune dysfunction.

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Section: Discussionsupporting

confidence: 71%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Effects of cigarette smoke extract on primary activated T cells

Hernandez

Morrow

Velasco

et al. 2013

Cellular Immunology

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“…ER stress is increased and HDAC activity is reduced in the lung by cigarette smoke exposure [8, 14, 25, 30, 31]. The present study employed pharmacological probes to induce ER stress and reduce HDAC activity.…”

Section: Discussionmentioning

confidence: 99%

Secretion of the endoplasmic reticulum stress protein, GRP78, into the BALF is increased in cigarette smokers

et al. 2017

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BackgroundIdentification of biomarkers of cigarette smoke –induced lung damage and early COPD is an area of intense interest. Glucose regulated protein of 78 kD (i.e., GRP78), a multi-functional protein which mediates cell responses to oxidant stress, is increased in the lungs of cigarette smokers and in the serum of subjects with COPD. We have suggested that secretion of GRP78 by lung cells may explain the increase in serum GRP78 in COPD. To assess GRP78 secretion by the lung, we assayed GRP78 in bronchoalveolar lavage fluid (BALF) in chronic smokers and non-smokers. We also directly assessed the acute effect of cigarette smoke material on GRP78 secretion in isolated human airway epithelial cells (HAEC).MethodsGRP78 was measured in BALF of smokers (S; n = 13) and non-smokers (NS; n = 11) by Western blotting. GRP78 secretion by HAEC was assessed by comparing its concentration in cell culture medium and cell lysates. Cells were treated for 24 h with either the volatile phase of cigarette smoke (cigarette smoke extract (CSE) or the particulate phase (cigarette smoke condensate (CSC)).ResultsGRP78 was present in the BALF of both NS and S but levels were significantly greater in S (p = 0.04). GRP78 was secreted constitutively in HAEC. CSE 15% X 24 h increased GRP78 in cell-conditioned medium without affecting its intracellular concentration. In contrast, CSC X 24 h increased intracellular GRP78 expression but did not affect GRP78 secretion. Brefeldin A, an inhibitor of classical Golgi secretion pathways, did not inhibit GRP78 secretion indicating that non-classical pathways were involved.ConclusionThe present study indicates that GRP78 is increased in BALF in cigarette smokers; that HAEC secrete GRP78; and that GRP78 secretion by HAEC is augmented by cigarette smoke particulates. Enhanced secretion of GRP78 by lung cells makes it a potential biomarker of cigarette smoke–induced lung injury.

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“…Moreover, pretreatment of lung epithelial cells with 14,15-EET decreased cigarette smoke extracts-induced expression of ER stress markers and was protective against apoptotic cell death [126]. The protective effects of epoxy fatty acids against ER stress seem to be accompanied with a reduction in mitochondrial dysfunction, inflammation and production of ROS, which are closely linked with ER stress [133]. In agreement with these observations, exogenous EETs, or CYP2J2 overexpression, inhibited mitochondrial dysfunction and decreased the levels of oxidative stress and cell apoptosis in lung tissues induced by ischemia/reperfusion in a human pulmonary artery endothelial cells [134].…”

Section: Modulation Of Er Stress By Soluble Epoxide Hydrolasementioning

confidence: 99%

Modulation of mitochondrial dysfunction and endoplasmic reticulum stress are key mechanisms for the wide-ranging actions of epoxy fatty acids and soluble epoxide hydrolase inhibitors

Inceoglu

Bettaieb

Haj

et al. 2017

Prostaglandins & Other Lipid Mediators

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The arachidonic acid cascade is arguably the most widely known biologic regulatory pathway. Decades after the seminal discoveries involving its cyclooxygenase and lipoxygenase branches, studies of this cascade remain an active area of research. The third and less widely known branch, the cytochrome P450 pathway leads to highly active oxygenated lipid mediators, epoxy fatty acids (EpFAs) and hydroxyeicosatetraenoic acids (HETEs), which are of similar potency to prostanoids and leukotrienes. Unlike the COX and LOX branches, no pharmaceuticals currently are marketed targeting the P450 branch. However, data support therapeutic benefits from modulating these regulatory lipid mediators. This is being approached by stabilizing or mimicking the EpFAs or even by altering the diet. These approaches lead to predominantly beneficial effects on a wide range of apparently unrelated states resulting in an enigma of how this small group of natural chemical mediators can have such diverse effects. EpFAs are degraded by soluble epoxide hydrolase (sEH) and stabilized by inhibiting this enzyme. In this review, we focus on interconnected aspects of reported mechanisms of action of EpFAs and inhibitors of soluble epoxide hydrolase (sEHI). The sEHI and EpFAs are commonly reported to maintain homeostasis under pathological conditions while remaining neutral under normal physiological conditions. Here we provide a conceptual framework for the unique and broad range of biological activities ascribed to epoxy fatty acids. We argue that their mechanism of action pivots on their ability to prevent mitochondrial dysfunction, to reduce subsequent ROS formation and to block resulting cellular signaling cascades, primarily the endoplasmic reticulum stress. By stabilizing the mitochondrial – ROS – ER stress axis, the range of activity of EpFAs and sEHI display an overlap with the disease conditions including diabetes, fibrosis, chronic pain, cardiovascular and neurodegenerative diseases, for which the above outlined mechanisms play key roles.

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Induction of CCAAT/enhancer-binding protein–homologous protein by cigarette smoke through the superoxide anion-triggered PERK–eIF2α pathway

Cited by 24 publications

References 36 publications

Effects of cigarette smoke extract on primary activated T cells

Effects of cigarette smoke extract on primary activated T cells

Secretion of the endoplasmic reticulum stress protein, GRP78, into the BALF is increased in cigarette smokers

Modulation of mitochondrial dysfunction and endoplasmic reticulum stress are key mechanisms for the wide-ranging actions of epoxy fatty acids and soluble epoxide hydrolase inhibitors

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