Toll-Like Receptor 4 Promotes NO Synthesis by Upregulating GCHI Expression under Oxidative Stress Conditions in Sheep Monocytes/Macrophages

Deng, Shoulong; Yu, Kun; Zhang, Baolu; Yao, Yuchang; Wang, Zhixian; Zhang, Jinlong; Zhang, Xiaosheng; Liu, Guoshi; Li, Ning; Liu, Yi‐Xun; Lian, Zhengxing

doi:10.1155/2015/359315

Cited by 21 publications

(17 citation statements)

References 45 publications

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“…Importantly, GTPCH1 expression is known to be increased in endothelial cells by enhanced NF-κB activity, a main target activated by TRAF-6 signaling3335. This pathway linking TLR-4 activation with enhanced GTPCH1 expression has been recently fully described in macrophages34. While this mechanism remains mainly speculative until further investigation, these data are in excellent agreement with the hypothesis of EDA as a modulator of eNOS coupling in diabetic aorta via TLR-4.…”

Section: Discussionsupporting

confidence: 80%

“…Moreover, this finding was associated with the upregulation of GTPCH1 expression, the main enzyme involved in the synthesis of the NOS coupling factor BH 4 (Fig. 5e and f), known to be increased after TLR-4-triggered NF-κB activity3435. However, no differences in both TRAF-6 and GTPCH1 expression levels were detected in STZ + EDA −/− compared to wild type (Fig.…”

Section: Resultsmentioning

confidence: 87%

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Lack of Fibronectin Extra Domain A Alternative Splicing Exacerbates Endothelial Dysfunction in Diabetes

Cappellari

Barazzoni

Cattin

et al. 2016

Sci Rep

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Glucose-induced changes of artery anatomy and function account for diabetic vascular complications, which heavily impact disease morbidity and mortality. Since fibronectin containing extra domain A (EDA + FN) is increased in diabetic vessels and participates to vascular remodeling, we wanted to elucidate whether and how EDA + FN is implicated in diabetes-induced endothelial dysfunction using isometric-tension recording in a murine model of diabetes. In thoracic aortas of EDA−/−, EDA+/+ (constitutively lacking and expressing EDA + FN respectively), and of wild-type mice (EDAwt/wt), streptozotocin (STZ)-induced diabetes impaired endothelial vasodilation to acetylcholine, irrespective of genotype. However STZ + EDA−/− mice exhibited increased endothelial dysfunction compared with STZ + EDA+/+ and with STZ + EDAwt/wt. Analysis of the underlying mechanisms revealed that STZ + EDA−/− mice show increased oxidative stress as demonstrated by enhanced aortic superoxide anion, nitrotyrosine levels and expression of NADPH oxidase NOX4 and TGF-β1, the last two being reverted by treatment with the antioxidant n-acetylcysteine. In contrast, NOX1 expression and antioxidant potential were similar in aortas from the three genotypes. Interestingly, reduced eNOS expression in STZ + EDA+/+ vessels is counteracted by increased eNOS coupling and function. Although EDA + FN participates to vascular remodelling, these findings show that it plays a crucial role in limiting diabetic endothelial dysfunction by preventing vascular oxidative stress.

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Section: Discussionsupporting

confidence: 80%

Section: Resultsmentioning

confidence: 87%

Lack of Fibronectin Extra Domain A Alternative Splicing Exacerbates Endothelial Dysfunction in Diabetes

Cappellari

Barazzoni

Cattin

et al. 2016

Sci Rep

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“…Amplified oxidative stress might decrease HDAC2 further as oxidative stress such as H 2 O 2 and cigarette smoke conditioned media are reported to decrease HDAC2 protein expression via protein modifications, such as phosphorylation, ubiquitination and nitration [11] , [38] , [39] . Notably, viral or bacterial infection or LPS exposure are reported to induce oxidative stress in cells [40] , [41] .…”

Section: Discussionmentioning

confidence: 99%

Repeated lipopolysaccharide exposure causes corticosteroid insensitive airway inflammation via activation of phosphoinositide-3-kinase δ pathway

Ueda

Nishimoto

Kimura

et al. 2016

Biochemistry and Biophysics Reports

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Corticosteroid resistance is one of major barriers to effective management of chronic inflammatory respiratory diseases, such as chronic obstructive pulmonary disease (COPD) and severe asthma. These patients often experience exacerbations with viral and/or bacterial infection, which may cause continuous corticosteroid insensitive inflammation. In this study, we observed that repeated exposure of lipopolysaccharide (LPS) intranasally attenuated the anti-inflammatory effects of the corticosteroid fluticasone propionate (FP) on neutrophils and CXCL1 levels in bronchoalveolar lavage (BAL) fluid in an in vivo murine model. Histone deacetylase-2 (HDAC2) and NF-E2 related factor 2 (Nrf2) levels in lungs after LPS administration for 3 consecutive days were significantly decreased to 38.9±6.3% (mean±SEM) and 77.5±2.7% of the levels seen after only one day of LPS exposure, respectively. In addition, 3 days LPS exposure resulted in an increase of Akt phosphorylation, indicating activation of the phosphoinositide-3-kinase (PI3K) pathway by 4-fold in lungs compared with 1 day of exposure. Furthermore, combination treatment with theophylline and FP significantly decreased the neutrophil accumulation and CXCL1 concentrations in BAL fluid from 22.5±1.8×104 cells/mL and 214.6±20.6 pg/mL to 7.9±0.5×104 cells/mL and 61.9±13.3 pg/mL, respectively. Combination treatment with IC87114, a selective PI3Kδ inhibitor, and FP also significantly decreased neutrophils and CXCL1 levels from 16.8±0.7×104 cells/mL and 182.4±4.6 pg/mL to 5.9±0.3×104 cells/mL and 71.4±2.7 pg/mL, respectively. Taken together, repeated exposure of LPS causes corticosteroid-insensitive airway inflammation in vivo, and the corticosteroid-resistance induced by LPS is at least partly mediated through the activation of PI3Kδ, resulting in decreased levels of HDAC2 and Nrf2. These findings provide a potentially new therapeutic approach to COPD and severe asthma.

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“…Our previous studies have shown that the immunocytes of TLR4-overexpressing transgenic sheep could trigger a more intense immune response to LPS stimulation, including the secretion of various interleukins, rapid neutrophil infiltration, and enhanced oxidative stress 31 - 33 . In our current study, we further surveyed whether the immunocytes of transgenic sheep influence bacterial internalization.…”

Section: Introductionmentioning

confidence: 99%

Overexpression of Toll-like Receptor 4-linked Mitogen-activated Protein Kinase Signaling Contributes to Internalization of Escherichia coli in Sheep

Wang¹,

Cao²,

Deng³

et al. 2018

Int. J. Biol. Sci.

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Escherichia coli is one of the most common causal pathogens of mastitis in milk-producing mammals. Toll-like receptor 4 (TLR4) is important for host recognition of this bacteria. Increased activation of TLR4 can markedly enhance the internalization of E. coli. In this study, the relationship between TLR4 and mitogen-activated protein kinase (MAPK) signaling pathways in mediating E. coli internalization was evaluated in sheep monocytes. Using a TLR4-overexpressing transgenic (Tg) sheep model, we explored the bacterial internalization mechanism in sheep. We found that monocytes of Tg sheep could phagocytize more bacteria and exhibited higher adhesive capacity. The specific inhibition of p38 MAPK or c-Jun N-terminal kinase (JNK) or extracellular signal-regulated kinases (ERKs) reduced TLR4-dependent internalization of bacteria into sheep monocytes. Furthermore, the inhibition of MAPK signaling down-regulated the adhesive capacity of monocytes and the expression of scavenger receptors and adhesion molecules. Taken together, the overexpression of TLR4 in transgenic sheep enhanced the internalization of E. coli via MAPK signaling.

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Toll-Like Receptor 4 Promotes NO Synthesis by Upregulating GCHI Expression under Oxidative Stress Conditions in Sheep Monocytes/Macrophages

Cited by 21 publications

References 45 publications

Lack of Fibronectin Extra Domain A Alternative Splicing Exacerbates Endothelial Dysfunction in Diabetes

Lack of Fibronectin Extra Domain A Alternative Splicing Exacerbates Endothelial Dysfunction in Diabetes

Repeated lipopolysaccharide exposure causes corticosteroid insensitive airway inflammation via activation of phosphoinositide-3-kinase δ pathway

Overexpression of Toll-like Receptor 4-linked Mitogen-activated Protein Kinase Signaling Contributes to Internalization of Escherichia coli in Sheep

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