Lung damage induced by hyperglycemia in diabetic rats: The role of signal transducer and activator of transcription 3 (STAT3)

Wang, Ching-Min; Hsu, Chao‐Tien; Niu, Ho‐Shan; Chang, Chin-Hong; Shieh, Jiunn‐Min

doi:10.1016/j.jdiacomp.2016.07.005

Cited by 32 publications

(39 citation statements)

References 30 publications

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“…This work demonstrates that PD-1 up-regulation is also profibrotic through its capacity to enhance STAT3 expression, leading to production of profibrotic cytokines, such as TGF-β and IL-17A. STATTIC inhibition of STAT3 has been shown to reduce collagen-1 content and connective tissue growth factor using the bleomycin murine model of pulmonary fibrosis (39–41). Furthermore, it has been previously demonstrated that genetic enhancement and ablation of STAT3 in the murine bleomycin model increase and reduce lung fibrosis, respectively (42).…”

Section: Discussionmentioning

confidence: 78%

PD-1 up-regulation on CD4 ⁺ T cells promotes pulmonary fibrosis through STAT3-mediated IL-17A and TGF-β1 production

et al. 2018

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Pulmonary fibrosis is a progressive inflammatory disease with high mortality and limited therapeutic options. Previous genetic and immunologic investigations suggest common intersections between idiopathic pulmonary fibrosis (IPF), sarcoidosis, and murine models of pulmonary fibrosis. To identify immune responses that precede collagen deposition, we conducted molecular, immunohistochemical, and flow cytometric analysis of human and murine specimens. Immunohistochemistry revealed programmed cell death-1 (PD-1) up-regulation on IPF lymphocytes. PD-1+CD4+ T cells with reduced proliferative capacity and increased transforming growth factor–β (TGF-β)/interleukin-17A (IL-17A) expression were detected in IPF, sarcoidosis, and bleomycin CD4+T Cells. PD-1+ T helper 17 cells are the predominant CD4+T cell subset expressing TGF-β. Coculture of PD-1+CD4+ T cells with human lung fibroblasts induced collagen-1 production. Strikingly, ex vivo PD-1 pathway blockade resulted in reductions in TGF-β and IL-17A expression from CD4+ T cells, with concomitant declines in collagen-1 production from fibroblasts. Molecular analysis demonstrated PD-1 regulation of the transcription factor STAT3 (signal transducer and activator of transcription 3). Chemical blockade of STAT3, using the inhibitor STATTIC, inhibited collagen-1 production. Both bleomycin administration to PD-1 null mice or use of antibody against programmed cell death ligand 1 (PD-L1) demonstrated significantly reduced fibrosis compared to controls. This work identifies a critical, previously unrecognized role for PD-1+CD4+ T cells in pulmonary fibrosis, supporting the use of readily available therapeutics that directly address interstitial lung disease pathophysiology.

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Section: Discussionmentioning

confidence: 78%

PD-1 up-regulation on CD4 ⁺ T cells promotes pulmonary fibrosis through STAT3-mediated IL-17A and TGF-β1 production

et al. 2018

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“…Nonspecific binding was blocked by incubation in 5% nonfat milk at room temperature for 2 h. Membranes were subsequently incubated with the primary antibodies (at 1:1,000 dilution) at 4˚C overnight, washed 3 times with TBST (0.05% Tween-20) and finally incubated with a HRP-conjugated secondary antibody at room temperature for 1 h. Protein bands were visualized using an chemiluminescence (ECL) kit (PerkinElmer, Inc., Waltham, MA, USA). The optical densities of the bands for calcineurin (18 kDa), NFAT3 (100 kDa), Histone H3 (15 kDa), and β-actin (43 kDa) were quantified using a laser densitometer (CHEM-400; Avegene Life Science, Taipei, Taiwan), as described in a previous study (28). The target antigens from the protein extracts were detected using primary antibodies specific for calcineurin (C0581; Sigma-Aldrich; Merck KGaA), NFAT3 (PA-1-021; Thermo Fisher Scientific, Inc.), or β-actin (A5441; Sigma-Aldrich; Merck KGaA) and Histone H3 (SC-8654; Cell Signaling Technology, Inc., Danvers, MA, USA).…”

Section: Reverse-transcription-quantitative Polymerase Chain Reactionmentioning

confidence: 99%

“…Nuclear extraction. The extraction of the nuclear fraction was performed according to a previously described method (28), using a CNMCS Compartmental Protein Extraction Kit (BioChain Institute, Inc., Hayward, CA, USA). Briefly, H9c2 cells were collected and ice-cold lysis buffer (2 ml per 20 million cells) added to them.…”

Section: Reverse-transcription-quantitative Polymerase Chain Reactionmentioning

confidence: 99%

Molecular mechanisms regarding potassium bromate‑induced cardiac hypertrophy without apoptosis in H9c2 cells

Kuo

Cheng

et al. 2018

Mol Med Report

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Cardiac hypertrophy is commonly involved in cardiac injury. Oxidative stress can induce cardiac hypertrophy with apoptosis. Potassium bromate (KBrO3) has been widely used as a food additive due to its oxidizing properties. In the present study, the rat‑derived heart cell line H9c2 was used to investigate the effect of KBrO3 on cell size. KBrO3 increased cell size at concentrations <250 µM, in a dose‑dependent manner. Additionally, KBrO3 also promoted the gene expression of two biomarkers of cardiac hypertrophy, brain/B‑type natriuretic peptides (BNP) and β‑Myosin Heavy Chain (β‑MHC). However, apoptosis remained unobserved in these cells. Moreover, mediation of free radicals was investigated using a fluorescence assay, and it was observed that superoxide and reactive oxygen species (ROS) levels increased with KBrO3. Effects of KBrO3 were significantly reduced by tiron at concentrations sufficient to produce antioxidant‑like action. Additionally, signals involved in cardiac hypertrophy such as calcineurin and nuclear factor of activated T‑cells (NFAT) were also determined using western blot analysis. KBrO3 increased the protein levels of both these molecules which were decreased by tiron in a dose‑dependent manner. Additionally, cyclosporine A attenuated the cardiac hypertrophy induced by KBrO3 in H9c2 cells at concentrations effective to inhibit calcineurin, in addition to reducing mRNA levels of BNP or β‑MHC. Finally, apoptosis was also identified in H9c2 cells incubated with KBrO3 at concentrations >300 µM. Collectively, these results provided a novel perspective that KBrO3 induces cardiac hypertrophy without apoptosis at a low dose through the generation of ROS, activating the calcineurin/NFAT signaling pathway in H9c2 cells. Therefore, at a dose <250 µM, KBrO3 can be applied as an inducer of cardiac hypertrophy without apoptosis in H9c2 cells. KBrO3 can also be developed as a tool to induce cardiac hypertrophy in animals.

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“…Furthermore, the activation of STAT3 may contribute to the transcriptional regulation of genes [20]. We previously demonstrated that the increase in STAT3 expression caused by hyperglycemia is involved in lung damage in diabetic rats [21]. Therefore, the role of STAT3 in the altered EPO response was also investigated in the present study.…”

mentioning

confidence: 78%

Investigation of the pronounced erythropoietin-induced reduction in hyperglycemia in type 1-like diabetic rats

Kuo

Cheng

et al. 2018

Endocr J

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Abstract. Erythropoietin (EPO) is known to stimulate erythropoiesis after binding with its specific receptor. In clinics, EPO is widely used in hemodialyzed patients with diabetes. However, changes in the expression of the erythropoietin receptor (EPOR) under diabetic conditions are still unclear. Therefore, we investigated EPOR expression both in vivo and in vitro. Streptozotocin-induced type 1-like diabetic rats (STZ rats) were used to evaluate the blood glucose-lowering effects of EPO. The expression and activity of the transducer and activator of transcription 3 (STAT3), the potential signaling molecule, was investigated in cultured rat skeletal myoblast (L6) cells incubated in high-glucose (HG) medium to mimic the in vivo changes. The EPO-induced reduction in hyperglycemia was more pronounced in diabetic rats. The increased EPOR expression in the soleus muscle of diabetic rats was reversed by the reduction in hyperglycemia. Glucose uptake was also increased in highglucose (HG)-treated L6 cells. Western blotting results indicated that the EPO-induced hyperglycemic activity was enhanced mainly through an increase in EPOR expression. Increased EPOR expression was associated with the enhanced nuclear expression of STAT3 in HG-exposed L6 cells. In addition, treatment with siRNA specific to STAT3 reversed the increased expression of EPOR observed in these cells. Treatment with Stattic at a dose sufficient to inhibit STAT3 reduced the expression level of EPOR in STZ rats. In conclusion, the increased expression of EPOR by hyperglycemia is mainly associated with an augmented expression of nuclear STAT3, which was identified both in vivo and in vitro in the present study. STZ rats, Streptozotocin-induced type 1-like diabetic rats; STAT3, transducer and activator of transcription 3; HG, high glucose; 2-NBDG, 2-(N-(7-Nitrobenz-2-oxa-1,3-diazol-4-yl)Amino)-2-Deoxyglucose; PBS, phosphate buffer solution; RIPA buffer, radioimmuno-precipitation assay buffer; HMBS, hydroxymethylbilane synthase

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Lung damage induced by hyperglycemia in diabetic rats: The role of signal transducer and activator of transcription 3 (STAT3)

Cited by 32 publications

References 30 publications

PD-1 up-regulation on CD4 ⁺ T cells promotes pulmonary fibrosis through STAT3-mediated IL-17A and TGF-β1 production

PD-1 up-regulation on CD4 ⁺ T cells promotes pulmonary fibrosis through STAT3-mediated IL-17A and TGF-β1 production

Molecular mechanisms regarding potassium bromate‑induced cardiac hypertrophy without apoptosis in H9c2 cells

Investigation of the pronounced erythropoietin-induced reduction in hyperglycemia in type 1-like diabetic rats

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Lung damage induced by hyperglycemia in diabetic rats: The role of signal transducer and activator of transcription 3 (STAT3)

Cited by 32 publications

References 30 publications

PD-1 up-regulation on CD4 + T cells promotes pulmonary fibrosis through STAT3-mediated IL-17A and TGF-β1 production

PD-1 up-regulation on CD4 + T cells promotes pulmonary fibrosis through STAT3-mediated IL-17A and TGF-β1 production

Molecular mechanisms regarding potassium bromate‑induced cardiac hypertrophy without apoptosis in H9c2 cells

Investigation of the pronounced erythropoietin-induced reduction in hyperglycemia in type 1-like diabetic rats

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PD-1 up-regulation on CD4 ⁺ T cells promotes pulmonary fibrosis through STAT3-mediated IL-17A and TGF-β1 production

PD-1 up-regulation on CD4 ⁺ T cells promotes pulmonary fibrosis through STAT3-mediated IL-17A and TGF-β1 production