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Liver kinase B1 is required for thromboxane receptor-dependent nuclear factor-?B activation and inflammatory responses.

ABSTRACT: Thromboxane A2 receptor (TPr) has been reported to trigger vascular inflammation. Nuclear factor ? B (NF-?B) is a known transcription factor. The aims of the present study were to determine the contributions of NF-?B activation to TPr-triggered vascular inflammation and elucidate the mechanism(s) underlying TPr activation of NF-?B.The effects of TPr activators, [1S-[1 alpha,2 alpha(Z),3beta(1E,3S*), 4 alpha]]-7-[3-[3-hydroxy-4-(4-iodophenoxy)-1-butenyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid (I-BOP) and U46619, on NF-?B activation, phosphorylation of rhoA/rho-associated kinases and liver kinase B1, cell adhesion and migration, proliferation, and endothelium-dependent vasorelaxation were assayed in cultured human umbilical vein endothelial cells, human monocytes, or isolated mouse aortas. Exposure of human umbilical vein endothelial cells to TPr agonists I-BOP and U46619 induced dose-dependent and time-dependent phosphorylation of inhibitor of ?B ? in parallel with aberrant expression of inflammatory markers cyclooxygenase-2, inducible nitric oxide synthase, intercellular adhesion molecule-1, and vascular cell adhesion molecule-1. Inhibition of NF-?B by pharmacological or genetic means abolished TPr-triggered expression of inflammatory markers. Consistently, exposure of human umbilical vein endothelial cells to either I-BOP or U46619 significantly increased phosphorylation of inhibitor of ?B ?, I kappaB kinase, rhoA, rho-associated kinases, and liver kinase B1. Pretreatment of human umbilical vein endothelial cells with the TPr antagonist SQ29548 or rho-associated kinases inhibitor Y27632 or silencing of the LKB1 blocked TPr-enhanced phosphorylation of inhibitor of ?B ? and its upstream kinase, I kappaB kinase. Finally, exposure of isolated mouse aortas to either U46619 or I-BOP enhanced NF-?B activation and vascular inflammation in parallel with reduced endothelium-dependent relaxation in intact vessels.TPr stimulation instigates aberrant inflammation and endothelial dysfunction via rho-associated kinases/liver kinase B1/I kappaB kinase-dependent NF-?B activation in vascular endothelial cells.

SUBMITTER: He J

PROVIDER: S-EPMC3868917 | biostudies-literature | 2013 Jun

REPOSITORIES: biostudies-literature

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Liver kinase B1 is required for thromboxane receptor-dependent nuclear factor-κB activation and inflammatory responses.

He Jinlong J Zhou Yanhong Y Xing Junjie J Wang Qilong Q Zhu Huaiping H Zhu Yi Y Zou Ming-Hui MH

Arteriosclerosis, thrombosis, and vascular biology 20130328 6

<h4>Objective</h4>Thromboxane A2 receptor (TPr) has been reported to trigger vascular inflammation. Nuclear factor κ B (NF-κB) is a known transcription factor. The aims of the present study were to determine the contributions of NF-κB activation to TPr-triggered vascular inflammation and elucidate the mechanism(s) underlying TPr activation of NF-κB.<h4>Approach and results</h4>The effects of TPr activators, [1S-[1 alpha,2 alpha(Z),3beta(1E,3S*), 4 alpha]]-7-[3-[3-hydroxy-4-(4-iodophenoxy)-1-bute ...[more]

PMID: 23539217

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Project description:The NF-κB pathway is a master regulator of inflammatory processes and is implicated in insulin resistance and pancreatic beta cell dysfunction in the metabolic syndrome. While canonical NF-κB signaling is well studied, there is little information on the divergent non-canonical NF-κB pathway in the context of pancreatic islet dysfunction in diabetes. Here, we demonstrate that pharmacological activation of the non-canonical NF-κB inducing kinase (NIK) disrupts glucose homeostasis in zebrafish in vivo. Further, we identify NIK as a critical negative regulator of beta cell function as pharmacological NIK activation results in impaired glucose-stimulated insulin secretion in mouse and human islets. NIK levels are elevated in pancreatic islets isolated from diet-induced obese (DIO) mice, which exhibit increased processing of non-canonical NF-κB components p100 to p52, and accumulation of RelB. Tumor necrosis factor α (TNFα) and receptor activator of NF-κB ligand (RANKL), two ligands associated with diabetes, induce NIK in islets. Mice with constitutive beta cell intrinsic NIK activation present impaired insulin secretion with DIO. NIK activation triggers the non-canonical NF-κB transcriptional network to induce genes identified in human type 2 diabetes genome-wide association studies linked to beta cell failure. These studies reveal that NIK contributes a central mechanism for beta cell failure in diet-induced obesity. We identify a role for Nuclear Factor inducing κB (NIK) in pancreatic beta cell failure. NIK activation disrupts glucose homeostasis in zebrafish in vivo and impairs glucose-stimulated insulin secretion in mouse and human islets in vitro. NIK activation also perturbs beta cell insulin secretion in a diet-induced obesity mouse model. These studies reveal that NIK contributes a central mechanism for beta cell failure in obesity. To uncover the role of NIK in pancreatic beta cells, we performed a gene expression microarray analysis comparing pancreatic islets with constitutive beta cell intrinsicNIK activation from the 16 week old mice (beta cell specific TRAF2 and TRAF2 knockout mice) to their controls (n=3 per group).

Project description:AimWe examined regulatory function of astaxanthin on mRNA expression of nuclear factor κB (NF-κB) p65, interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-α), and interferon gamma (IFN-γ) in peripheral blood mononuclear cells in pre and postpartum Murrah buffaloes during summer (temperature-humidity index [THI]=86; relative humidity [RH]=24) and winter (THI=58.74; RH=73) seasons.Materials and methodsA total of 32 Murrah buffaloes apparently healthy and in their one to four parity were selected from National Dairy Research Institute herd and equally distributed randomly into four groups (control and supplemented groups of buffaloes during summer and winter season, respectively). All groups were fed according to the nutrient requirement of buffaloes (ICAR, 2013). The treatment group was supplemented with astaxanthin at 0.25 mg/kg body weight/animal/day during the period 30 days before expected date of calving and up to 30 days postpartum.ResultsThere was downregulation of NF-κB p65 gene in all the groups. NF-κB p65 mRNA expression was lower (p<0.05) in treatment than control group from prepartum to postpartum during summer, while mRNA expression was low only on day 21 after calving during winter season. The mRNA expression of IL-6, TNF-α, and IFN-γ was lower (p<0.05) in treatment than a control group of buffaloes during summer and winter seasons. The mRNA expression of NFkB p65, IL-6, TNF-α, and IFN-γ was higher (p<0.05) in summer than in winter seasons.ConclusionThe xanthophyll carotenoid astaxanthin a reddish-colored C-40 compound is a powerful broad-ranging antioxidant that naturally occurs in a wide variety of living organisms, such as microalgae, fungi, crustaceans, and complex plants. Astaxanthin blocked nuclear translocation of NF-κB p65 subunit and IκBα degradation, which correlated with its inhibitory effect on IκB kinase (IKK) activity. These results suggest that astaxanthin, probably due to its antioxidant activity, inhibits the production of inflammatory mediators by blocking NF-κB activation and as a consequent suppression of IKK activity and IκB-degradation.

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Liver kinase B1 is required for thromboxane receptor-dependent nuclear factor-?B activation and inflammatory responses.

Publications

Liver kinase B1 is required for thromboxane receptor-dependent nuclear factor-κB activation and inflammatory responses.

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