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Inhibition of endoplasmic reticulum stress alleviates lipopolysaccharide-induced lung inflammation through modulation of NF-?B/HIF-1? signaling pathway.

ABSTRACT: Lipopolysaccharide (LPS) is involved in a variety of inflammatory disorders. Under stress conditions, endoplasmic reticulum (ER) loses the homeostasis in its functions, which is defined as ER stress. Little is known how ER stress is implicated in LPS-induced lung inflammation. In this study, effects of inhibition of ER stress on LPS-induced lung inflammation and transcriptional regulation were examined. An ER stress regulator, 4-phenylbutyrate (PBA) reduced LPS-induced increases of various ER stress markers in the lung. Furthermore, inhibition of ER stress reduced the LPS-induced lung inflammation. Moreover, LPS-induced increases of NF-?B and HIF-1? activity were lowered by inhibition of ER stress. These results suggest that inhibition of ER stress ameliorates LPS-induced lung inflammation through modulation of NF-?B/I?B and HIF-1? signaling pathway.

SUBMITTER: Kim HJ

PROVIDER: S-EPMC3556596 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Inhibition of endoplasmic reticulum stress alleviates lipopolysaccharide-induced lung inflammation through modulation of NF-κB/HIF-1α signaling pathway.

Kim Hee Jung HJ Jeong Jae Seok JS Kim So Ri SR Park Seung Yong SY Chae Han Jung HJ Lee Yong Chul YC

Scientific reports 20130128

Lipopolysaccharide (LPS) is involved in a variety of inflammatory disorders. Under stress conditions, endoplasmic reticulum (ER) loses the homeostasis in its functions, which is defined as ER stress. Little is known how ER stress is implicated in LPS-induced lung inflammation. In this study, effects of inhibition of ER stress on LPS-induced lung inflammation and transcriptional regulation were examined. An ER stress regulator, 4-phenylbutyrate (PBA) reduced LPS-induced increases of various ER st ...[more]

PMID: 23359618

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Project description:Background:Both endoplasmic reticulum (ER) stress and macrophage diversity contribute to inflammatory processes in lung injury. However, the interaction between ER stress and macrophage M1/M2 imbalance in lung inflammation remains unclear. The present study, thus, aimed to evaluate the role of ER stress-mediated macrophage phenotype changes in lipopolysaccharide (LPS)-induced acute lung injury (ALI). Methods:Lung inflammation and injury were examined in a murine model of LPS-induced ALI with or without ER stress inhibitors. Alveolar macrophage (AM) polarization was determined by flow cytometry. Bone marrow-derived macrophages (BMDMs) were treated with either an ER stress inducer, inhibitor, or an IRE-1 endonuclease inhibitor before being polarized to an M1 and M2 phenotype. The macrophage polarization status was examined via RT-PCR and flow cytometry. Results:Our results indicated that ER stress and IRE-1/XBP-1 signaling are activated in LPS-induced ALI. Furthermore, we observed that AM polarizes to an inflammatory phenotype upon exposure to LPS in the induction phase and an anti-inflammatory phenotype in the resolution phase of lung inflammation. Inhibition of ER stress attenuated the pathophysiological features of LPS-induced lung inflammation/injury, as evidenced by a decrease in bronchoalveolar lavage (BAL) protein levels, the number of inflammatory cells, and the expression level of inflammatory mediators. In addition, the ER stress inducer promoted M1 polarization and the switch from M2 to M1 in BMDMs, whereas inhibition of ER stress and XBP-1 splicing suppressed M1 but did not promote M2, both in vivo and in vitro. Conclusions:Our results demonstrated that inhibition of the ER stress-associated IRE-1/XBP-1 signaling pathway suppresses M1 polarization and ameliorates LPS-induced lung injury. This indicates that the interaction between ER stress and macrophage polarization might be a novel therapeutic target for endotoxin-induced lung inflammatory disorders.

Project description:BackgroundPapaver nudicaule belongs to the Papaveraceae family, which is planted as an annual herbaceous species generally for ornamental purpose. Papaver rhoeas in the same family has been reported to have various pharmacological activities such as antioxidant and analgesic effects. In contrast, little is known about the pharmacological activity of Papaver nudicaule. In this study, the anti-inflammatory activity of Papaver nudicaule extracts and the action mechanisms were investigated in RAW264.7 macrophage cells.MethodsTo investigate the anti-inflammatory activity of five cultivars of Papaver nudicaule with different flower color, samples were collected from their aerial parts at two growth stages (60 and 90 days) and their ethanol extracts were evaluated in the lipopolysaccharide (LPS)-treated RAW264.7 cells by measuring nitric oxide (NO) and prostaglandin E2 (PGE2) levels. Interleukin 1-beta (IL-1β), Interleukin-6 (IL-6) and Tumor necrosis factor alpha (TNF-α) production were also analyzed by RT-PCR and multiplex assays. Nuclear Factor-kappa-light-chain-enhancer of activated B cells (NF-κB) and Signal transducer and activator of transcription 3 (STAT3) signaling pathways were examined using western blotting and luciferase reporter assays to reveal the action mechanism of Papaver nudicaule extracts in their anti-inflammatory activity.ResultsAll of the Papaver nudicaule extracts were effective in reducing the LPS-induced NO, which is an important inflammatory mediator, and the extract of Papaver nudicaule with white flower collected at 90 days (NW90) was selected for further experiments because of the best effect on reducing the LPS-induced NO as well as no toxicity. NW90 lowered the LPS-induced PGE2 level and decreased the LPS-induced Nitric oxide synthase 2 (NOS2) and Cyclooxygenase 2 (COX2). In addition, NW90 reduced the LPS-induced inflammatory cytokines, IL-1β and IL-6. Furthermore, NW90 inhibited the LPS-induced activation of NF-κB and STAT3.ConclusionsThese results indicate that NW90 may restrain inflammation by inhibiting NF-κB and STAT3, suggesting the potential therapeutic properties of Papaver nudicaule against inflammatory disease.

Project description:Fine particulate matter (PM2.5) is a type of small particle that is <2.5 µm in diameter that may cause airway inflammation. Thus, the present study aimed to explore the effects of PM2.5 on endoplasmic reticulum (ER) stress and airway inflammation in human airway epithelial cells. For this purpose, HBE135‑E6E7 airway epithelial cells were cultured and exposed to specific concentrations of PM2.5 for various periods of time, and cell viability was determined using a Cell Counting Kit‑8 assay. The results of the present study demonstrated that exposure to PM2.5 increased the mRNA and protein expression levels of interleukin (IL)‑6, tumor necrosis factor (TNF)‑α and mucin 5AC (MUC5AC). Moreover, the expression levels of ER stress‑related proteins, such as glucose‑regulated protein 78, CCAAT‑enhancer binding protein homologous protein, activating transcription factor 6, protein kinase R‑like ER kinase (PERK), phosphorylated (p‑)PERK, inositol‑requiring enzyme 1α (IRE1α) and p‑IRE1α, and nucleotide‑binding oligomerization domain 1 (NOD1) expression levels were increased following exposure to PM2.5. Transfection with IRE1α small interfering RNA (siRNA) led to the increased production of IL‑6, TNF‑α and MUC5AC. Moreover, the expression of NOD1 and the translocation of NF‑κB p65 were inhibited following transfection with IRE1α siRNA. In addition, the results of the present study demonstrated that transfection with NOD1 siRNA decreased the production of IL‑6, TNF‑α and MUC5AC, and decreased the translocation of NF‑κB p65. The expression levels of IL‑6, TNF‑α and MUC5AC were increased in the HBE135‑E6E7 cells following treatment with C12‑iE‑DAP, a NOD1 agonist. Moreover, treatment with C12‑iE‑DAP led to the activation of NF‑κB p65. Collectively, the results of the present study suggest that PM2.5 promotes airway inflammation and mucin production by activating ER stress in HBE135‑E6E7 airway epithelial cells, and that the IRE1α/NOD1/NF‑κB pathway may be involved in this process.

Dataset Information

Inhibition of endoplasmic reticulum stress alleviates lipopolysaccharide-induced lung inflammation through modulation of NF-?B/HIF-1? signaling pathway.

Publications

Inhibition of endoplasmic reticulum stress alleviates lipopolysaccharide-induced lung inflammation through modulation of NF-κB/HIF-1α signaling pathway.

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