Lipopolysaccharide Induces Lung Fibroblast Proliferation through Toll-Like Receptor 4 Signaling and the Phosphoinositide3-Kinase-Akt Pathway

He, Zhengyu; Gao, Yuan; Deng, Yuxiao; Wen, Lan; Chen, Yongming; Xing, Shunpeng; Zhao, Xianyuan; Ding, Jia; Wang, Xiangrui

doi:10.1371/journal.pone.0035926

Cited by 74 publications

(65 citation statements)

References 37 publications

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“…HMGB1 activates inflammatory pathways by stimulating TLR4 in many types of tissue injuries. 42,43 Our previous work, [22][23][24] as well as the work of others, [25][26][27] indicated that TLR4 mediates many forms of ALI, such as hemorrhagic shock-induced ALI and LPS-induced ALI. Overexpression of TLR4 in the lung tissue amplifies the severity of LPS-induced ALI.…”

Section: Discussionmentioning

confidence: 94%

“…[19][20][21] We have previously demonstrated that the activation of TLR4 and its downstream intracellular signal-transduction pathways is crucial to lipopolysaccharide (LPS)-induced ALI. [22][23][24] Other studies also reported that TLR4 mutant (C3H/HeJ) mice developed less ALI after unresuscitated hemorrhagic shock or being challenged with LPS. 25,26 Conversely, the overexpression of TLR4 in transgenic mice aggravated ALI and pulmonary inflammation, endothelial cell damage, and the recruitment of neutrophils to the lung.…”

mentioning

confidence: 97%

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TLR4 as receptor for HMGB1-mediated acute lung injury after liver ischemia/reperfusion injury

Yang

Deng

et al. 2013

Laboratory Investigation

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Acute lung injury (ALI) frequently occurs after liver transplantation and major liver surgery. Proinflammatory mediators released by damaged liver after liver ischemia/reperfusion (I/R) injury might contribute to this form of ALI, but the underlying mechanisms have not been well characterized. High-mobility group box protein 1 (HMGB1), a recently identified proinflammatory cytokine, was found to be significantly higher in the serum after liver I/R injury. This study investigated whether HMGB1 was involved as a stimulating factor, and whether its downstream Toll-like receptor 4 (TLR4), p38 mitogen-activated protein kinase (p38MAPK), and activator protein-1 (AP-1) signaling pathways act as mediators in the development of liver I/R injury-induced ALI. Extensive ALI and lung inflammation was induced in a rat model of liver I/R injury. Serum HMGB1 was significantly higher after liver I/R injury, and more importantly, expression of HMGB1 mRNA and protein in the lung tissue was also significantly increased. We further found that liver I/R injury enhanced the expression of TLR4 mRNA and protein, and the activity of p38MAPK and AP-1 in the lung tissue. Inhibition of TLR4 expression in the lung tissue by infection with pGCSIL-GFP-lentivirus-expressing small hairpin RNAs targeting the TLR4 gene (TLR4-shRNA lentivirus) significantly attenuated ALI, lung inflammation, and activity of p38MAPK and AP-1 in the lung tissue. These findings indicate that HMGB1 might contribute to the underlying mechanism for liver I/R injuryinduced ALI and that its downstream TLR4, p38MAPK, and AP-1 signaling pathways are potentially important mediators in the development of ALI.

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Section: Discussionmentioning

confidence: 94%

mentioning

confidence: 97%

TLR4 as receptor for HMGB1-mediated acute lung injury after liver ischemia/reperfusion injury

Yang

Deng

et al. 2013

Laboratory Investigation

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“…As the specific receptor of LPS, TLR4 plays a critical role in LPS-induced ALI and pulmonary fibrosis. Previous studies have shown that TLR4 is required for LPS-associated lung fibroblast activation 12 and proliferation, 14,17 lung inflammatory reaction, 18,19 and pulmonary fibrosis. 1 In agreement with these published findings, our present study demonstrated that upregulation of TLR4 by LPS accounted for LPS-induced proliferation in mouse lung fibroblasts (MIC-CELL-0040) that could be restored by siRNA-mediated TLR4 silencing, suggesting that TLR4 is essential for LPS-induced Thy-1 gene silencing in lung fibroblasts and cell proliferation.…”

Section: Discussionmentioning

confidence: 97%

“…TLR4 mRNA ( Figure 1a) and protein ( Figure 1b) levels were significantly reduced in lung fibroblasts after infection with 1 × 10 8 TUs/ml TLR4-siRNA-lentivirus for 48 h. Challenge of lung fibroblasts with LPS led to significant upregulation of TLR4 mRNA and protein expression (Po0.05); however, pretreatment with TLR4-siRNA-lentivirus followed by LPS challenge still decreased the TLR4 mRNA and protein to levels of TLR4-siRNA-lentivirus infection alone (Po0.05), indicating that TLR4 is a downstream target of LPS signaling pathway and providing an additional evidence for the notion that TLR4 plays an important role in LPS-induced proliferation of primary cultured mouse lung fibroblasts. 10,14 To extend these observations, we further measured cell proliferation and cell-cycle progression of lung fibroblasts after TLR4 silencing in the presence or absence of LPS challenge for different time points by MTT assay and flow cytometry, respectively. Compared with controls, LPS significantly increased lung fibroblast proliferation ( Figure 1c) and the number of cells in the S phase ( Figure 1d) 48-72 h after challenge (Po0.05).…”

Section: Silencing Of Tlr4 Inhibits Lps-enhanced Proliferation Of Lunmentioning

confidence: 99%

HDAC is essential for epigenetic regulation of Thy-1 gene expression during LPS/TLR4-mediated proliferation of lung fibroblasts

Xing

Nie

et al. 2015

Laboratory Investigation

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Lipopolysaccharide (LPS)-induced proliferation of lung fibroblasts is closely correlated with loss of gene expression of thymocyte differentiation antigen-1 (Thy-1), accompanied with deacetylation of histones H3 and H4 at the Thy-1 gene promoter region; however, the mechanism remains enigmatic. We report here that LPS downregulates Thy-1 gene expression by activating histone deacetylases (HDACs) via Toll-like receptor 4 (TLR4) signaling. Treatment of primary cultured mouse lung fibroblasts with LPS resulted in significant upregulation of TLR4 and enhanced cell proliferation that was abolished by silencing TLR4 with lentivirus-delivered TLR4 shRNA. Interestingly, LPS increased the mRNA and protein levels of HDAC-4, -5, and -7, an effect that was abrogated by HDAC inhibitor trichostatin A (TSA) or TLR4-shRNA-lentivirus. Consistent with these findings, Ace-H3 and Ace-H4 were decreased by LPS that was prevented by TSA. Most importantly, chromosome immunoprecipitation (ChIP) analysis demonstrated that LPS decreased the association of Ace-H4 at the Thy-1 promoter region that was efficiently restored by pretreatment with TSA. Accordingly, LPS decreased the mRNA and protein levels of Thy-1 that was inhibited by TSA. Furthermore, silencing the Thy-1 gene by lentivirus-delivered Thy-1 shRNA could promote lung fibroblast proliferation, even in the absence of LPS. Conversely, overexpressing Thy-1 gene could inhibit lung fibroblast proliferation and reduce LPS-induced lung fibroblast proliferation. Our data suggest that LPS upregulates and activates HDACs through TLR4, resulting in deacetylation of histones H3 and H4 at the Thy-1 gene promoter that may contribute to Thy-1 gene silencing and lung fibroblast proliferation. Pulmonary fibrosis is characterized by aberrant proliferation and activation of lung fibroblasts. 1,2 The phenotypic transition of lung fibroblasts during the process of pulmonary fibrosis can be stimulated by various pathological conditions, including lipopolysaccharide (LPS), a component of bacteria membranes and an important player during the development of pulmonary fibrosis. 3,4 LPS-induced proliferation of lung fibroblast is associated with the silencing of thymocyte differentiation antigen-1 (Thy-1) and deacetylation of histones H3 and H4 at the Thy-1 gene promoter; 5,6 however, the mechanism by which LPS promotes the deacetylation of histones H3 and H4 leading to downregulation of Thy-1 gene expression is largely unknown.Thy-1 is a cell surface glycoprotein that is present in normal lung fibroblasts but absent from the fibroblastic foci of idiopathic pulmonary fibrosis (IPF). 7 Heterogeneous surface expression of Thy-1 in fibroblasts results in the specialization of fibroblast, including Thy-1 (+) and Thy-1 (− ) subsets. Hagood et al 5,8,9 reported that lack of Thy-1 expression on lung fibroblasts contributed to IPF. Recently, it was found that epigenetic mechanisms, such as promoter hypermethylation and histone modification, play an important role in Thy-1 gene silencing in lung fibroblasts. 6,7 Our...

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“…Specifically, TLR4 signaling plays a central role in macrophage activation in both septic and aseptic inflammation, including ARDS (32,33,(51)(52)(53)(54)(55), and is critical in the pathogenesis of disease (12,32,55). TLR4 signaling is controlled by MyD88-or TRIF-dependent downstream effectors, the signals of which converge for TRAF6 activation and NF-kB nuclear translocation (56).…”

Section: Discussionmentioning

confidence: 99%

Akt2 Deficiency Protects from Acute Lung Injury via Alternative Macrophage Activation and miR-146a Induction in Mice

Vergadi

Vaporidi

Theodorakis

et al. 2014

The Journal of Immunology

142

106

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Acute respiratory distress syndrome (ARDS) is a major cause of respiratory failure, with limited effective treatments available. Alveolar macrophages participate in the pathogenesis of ARDS. To investigate the role of macrophage activation in aseptic lung injury and identify molecular mediators with therapeutic potential, lung injury was induced in wild-type (WT) and Akt2−/− mice by hydrochloric acid aspiration. Acid-induced lung injury in WT mice was characterized by decreased lung compliance and increased protein and cytokine concentration in bronchoalveolar lavage fluid. Alveolar macrophages acquired a classical activation (M1) phenotype. Acid-induced lung injury was less severe in Akt2−/− mice compared with WT mice. Alveolar macrophages from acid-injured Akt2−/− mice demonstrated the alternative activation phenotype (M2). Although M2 polarization suppressed aseptic lung injury, it resulted in increased lung bacterial load when Akt2−/− mice were infected with Pseudomonas aeruginosa. miR-146a, an anti-inflammatory microRNA targeting TLR4 signaling, was induced during the late phase of lung injury in WT mice, whereas it was increased early in Akt2−/− mice. Indeed, miR-146a overexpression in WT macrophages suppressed LPS-induced inducible NO synthase (iNOS) and promoted M2 polarization, whereas miR-146a inhibition in Akt2−/− macrophages restored iNOS expression. Furthermore, miR-146a delivery or Akt2 silencing in WT mice exposed to acid resulted in suppression of iNOS in alveolar macrophages. In conclusion, Akt2 suppression and miR-146a induction promote the M2 macrophage phenotype, resulting in amelioration of acid-induced lung injury. In vivo modulation of macrophage phenotype through Akt2 or miR-146a could provide a potential therapeutic approach for aseptic ARDS; however, it may be deleterious in septic ARDS because of impaired bacterial clearance.

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Lipopolysaccharide Induces Lung Fibroblast Proliferation through Toll-Like Receptor 4 Signaling and the Phosphoinositide3-Kinase-Akt Pathway

Cited by 74 publications

References 37 publications

TLR4 as receptor for HMGB1-mediated acute lung injury after liver ischemia/reperfusion injury

TLR4 as receptor for HMGB1-mediated acute lung injury after liver ischemia/reperfusion injury

HDAC is essential for epigenetic regulation of Thy-1 gene expression during LPS/TLR4-mediated proliferation of lung fibroblasts

Akt2 Deficiency Protects from Acute Lung Injury via Alternative Macrophage Activation and miR-146a Induction in Mice

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