Insulin-Dependent Phosphatidylinositol 3-Kinase/Akt and ERK Signaling Pathways Inhibit TLR3-Mediated Human Bronchial Epithelial Cell Apoptosis

Numata, Takanori; Araya, Jun; Fujii, Satoko; Hara, Hiromichi; Takasaka, Naoki; Kojima, Jun; Minagawa, Shunsuke; Yumino, Yoko; Kawaishi, Makoto; Hirano, Jun; Odaka, Makoto; Morikawa, Toshiaki; Nishimura, Stephen L.; Nakayama, Katsutoshi; Kuwano, Kazuyoshi

doi:10.4049/jimmunol.1004218

Cited by 28 publications

(23 citation statements)

References 40 publications

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“…We also did not find any increase in the expression of the well-described FOXO target gene Bim, a proapoptotic factor of the Bcl-2 family that is induced upon several stress stimuli (24). Numata et al (36) reported that treatment of insulin-depleted HBEC with 10 mg/ml Poly-(I:C) leads to apoptosis via TLR3. The authors did not investigate the role of FOXO in these findings, but, considering our data, FOXO is a potential coeffector.…”

Section: Discussionmentioning

confidence: 99%

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FOXO Transcription Factors Regulate Innate Immune Mechanisms in Respiratory Epithelial Cells

Seiler

Hellberg

Lepper

et al. 2013

The Journal of Immunology

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Bacterial pathogens are a leading cause of lung infections and contribute to acute exacerbations in patients with chronic respiratory diseases. The innate immune system of the respiratory tract controls and prevents colonization of the lung with bacterial pathogens. Forkhead box transcription factor family O (FOXO) transcription factors are key regulators of cellular metabolism, proliferation, and stress resistance. In this study, our aim was to investigate the role of FOXO transcription factors in innate immune functions of respiratory epithelial cells. We show that bacterial pathogens potently activate FOXO transcription factors in cultured human respiratory epithelial cells in vitro. Infection of mice with bacterial pathogens resulted in the activation of FOXO transcription factors in alveolar and bronchial epithelial cells in vivo. Active FOXO was also detectable in human bronchial tissue obtained from subjects with different infection-related lung diseases. Small interfering RNA–mediated knockdown of FOXO in bronchial epithelial cells resulted in reduced expression of factors of the innate immune system such as antimicrobial peptides and proinflammatory cytokines, both under basal conditions and upon infection. FOXO deficiency further affected internalization of Haemophilus influenzae in bronchial epithelial cells. Finally, we show that TLR3 activates innate immune responses in a FOXO-dependent manner. In conclusion, FOXO transcription factors are involved in the cellular responses to bacterial stimuli and act as central regulators of innate immune functions in respiratory epithelial cells.

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Section: Discussionmentioning

confidence: 99%

“…However, there was no difference in TLR3 transcription between knockdown and control cells. In a former study, it has been shown that Poly-(I:C) at 10 mg/ml induces TLR3-dependent cell death in respiratory epithelial cells (36). Therefore we assessed if cell death occurs in our particular setting.…”

Section: Foxo Mediates Tlr-3 Signalingmentioning

confidence: 99%

FOXO Transcription Factors Regulate Innate Immune Mechanisms in Respiratory Epithelial Cells

Seiler

Hellberg

Lepper

et al. 2013

The Journal of Immunology

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“…Cell cycle analysis and flow cytometry were performed as previously described [18]. Briefly, treated cells were harvested and immediately immobilized by 70% ice-cold ethanol overnight.…”

Section: Methodsmentioning

confidence: 99%

Apoptosis inhibitor of macrophage (AIM) expression in alveolar macrophages in COPD

et al. 2013

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BackgroundMarked accumulation of alveolar macrophages (AM) conferred by apoptosis resistance has been implicated in pathogenesis of chronic obstructive pulmonary disease (COPD). Apoptosis inhibitor of macrophage (AIM), has been shown to be produced by mature tissue macrophages and AIM demonstrates anti-apoptotic property against multiple apoptosis-inducing stimuli. Accordingly, we attempt to determine if AIM is expressed in AM and whether AIM is involved in the regulation of apoptosis in the setting of cigarette smoke extract (CSE) exposure.MethodsImmunohistochemical evaluations of AIM were performed. Immunostaining was assessed by counting total and positively staining AM numbers in each case (n = 5 in control, n = 5 in non-COPD smoker, n = 5 in COPD). AM were isolated from bronchoalveolar lavage fluid (BALF). The changes of AIM expression levels in response to CSE exposure in AM were evaluated. Knock-down of anti-apoptotic Bcl-xL was mediated by siRNA transfection. U937 monocyte-macrophage cell line was used to explore the anti-apoptotic properties of AIM.ResultsThe numbers of AM and AIM-positive AM were significantly increased in COPD lungs. AIM expression was demonstrated at both mRNA and protein levels in isolated AM, which was enhanced in response to CSE exposure. AIM significantly increased Bcl-xL expression levels in AM and Bcl-xL was involved in a part of anti-apoptotic mechanisms of AIM in U937 cells in the setting of CSE exposure.ConclusionsThese results suggest that AIM expression in association with cigarette smoking may be involved in accumulation of AM in COPD.

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“…Immunofluorescence staining was performed as previously described (21). The primary Abs were applied according to the manufacturer's instructions.…”

Section: Preparation Of Csementioning

confidence: 99%

Autophagy Induction by SIRT6 through Attenuation of Insulin-like Growth Factor Signaling Is Involved in the Regulation of Human Bronchial Epithelial Cell Senescence

Takasaka

Araya

Hara

et al. 2014

The Journal of Immunology

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163

145

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Cigarette smoke (CS)–induced cellular senescence has been implicated in the pathogenesis of chronic obstructive pulmonary disease, and SIRT6, a histone deacetylase, antagonizes this senescence, presumably through the attenuation of insulin-like growth factor (IGF)-Akt signaling. Autophagy controls cellular senescence by eliminating damaged cellular components and is negatively regulated by IGF-Akt signaling through the mammalian target of rapamycin (mTOR). SIRT1, a representative sirtuin family, has been demonstrated to activate autophagy, but a role for SIRT6 in autophagy activation has not been shown. Therefore, we sought to investigate the regulatory role for SIRT6 in autophagy activation during CS-induced cellular senescence. SIRT6 expression levels were modulated by cDNA and small interfering RNA transfection in human bronchial epithelial cells (HBECs). Senescence-associated β-galactosidase staining and Western blotting of p21 were performed to evaluate senescence. We demonstrated that SIRT6 expression levels were decreased in lung homogenates from chronic obstructive pulmonary disease patients, and SIRT6 expression levels correlated significantly with the percentage of forced expiratory volume in 1 s/forced vital capacity. CS extract (CSE) suppressed SIRT6 expression in HBECs. CSE-induced HBEC senescence was inhibited by SIRT6 overexpression, whereas SIRT6 knockdown and mutant SIRT6 (H133Y) without histone deacetylase activity enhanced HBEC senescence. SIRT6 overexpression induced autophagy via attenuation of IGF-Akt-mTOR signaling. Conversely, SIRT6 knockdown and overexpression of a mutant SIRT6 (H133Y) inhibited autophagy. Autophagy inhibition by knockdown of ATG5 and LC3B attenuated the antisenescent effect of SIRT6 overexpression. These results suggest that SIRT6 is involved in CSE-induced HBEC senescence via autophagy regulation, which can be attributed to attenuation of IGF-Akt-mTOR signaling.

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Insulin-Dependent Phosphatidylinositol 3-Kinase/Akt and ERK Signaling Pathways Inhibit TLR3-Mediated Human Bronchial Epithelial Cell Apoptosis

Cited by 28 publications

References 40 publications

FOXO Transcription Factors Regulate Innate Immune Mechanisms in Respiratory Epithelial Cells

FOXO Transcription Factors Regulate Innate Immune Mechanisms in Respiratory Epithelial Cells

Apoptosis inhibitor of macrophage (AIM) expression in alveolar macrophages in COPD

Autophagy Induction by SIRT6 through Attenuation of Insulin-like Growth Factor Signaling Is Involved in the Regulation of Human Bronchial Epithelial Cell Senescence

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