Dataset Information

Adrenoceptor-stimulated inflammatory response in stress-induced serum amyloid A synthesis.

ABSTRACT: RATIONALE:Stressful life events are suggested to contribute to the development of various pathologies, such as cardiovascular disorders, whose etiopathogenesis is highly associated with elevated levels of serum amyloid A (SAA) proteins. SAA synthesis in the liver is regulated by a complex network of cytokines acting independently or in concert with various hormones/stimulants including the stress-activated sympathetic nervous system. OBJECTIVE:This study aims to investigate the underlying mechanisms that regulate the stress-induced hepatic synthesis of SAA, with particular focus on adrenoceptors (AR), major components of the sympathoadrenal response to stress. METHODS AND RESULTS:We demonstrated that repeated stress elevates IL-1?, IL-6, and TNF? serum levels in mice, accompanied by increased synthesis and secretion of hepatic SAA1/2 and SAA3, an effect that was blocked by AR antagonists. Moreover, stimulation of ?1- and ?1/2-ARs mimics the stress effect on SAA1/2 regulation, whereas ?2-AR stimulation exhibits a relatively weak impact on SAA. In support of the essential cytokine contribution in the AR-agonist induced SAA production is the fact that the anti-inflammatory drug, sodium salicylate, prevented the AR-stimulated hepatic SAA1/2 synthesis by reducing IL-1? levels, whereas IL-1? inhibition with Anakinra mimics this sodium salicylate preventive effect, thus indicating a crucial role for IL-1?. Interestingly, the AR-driven SAA3 synthesis was elevated by sodium salicylate in a TNF?-dependent way, supporting diverse and complex regulatory roles of cytokines in SAA production. In contrast to ?1/?2-AR, the ?1/2-AR-mediated SAA1/2 and SAA3 upregulation cannot be reversed by fenofibrate, a hypolipidemic drug with anti-inflammatory properties. CONCLUSION:Taken together, these findings strongly support a critical role of the AR-stimulated inflammatory response in the hepatic SAA production under stressful conditions, highlighting distinct AR type-specific mechanisms that regulate the hepatic synthesis of SAA1/2 and SAA3.

SUBMITTER: Konstandi M

PROVIDER: S-EPMC6643287 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Adrenoceptor-stimulated inflammatory response in stress-induced serum amyloid A synthesis.

Konstandi Maria M Sotiropoulos Ioannis I Matsubara Tsutomu T Malliou Foteini F Katsogridaki Alexandra A Andriopoulou Christina E CE Gonzalez Frank J FJ

Psychopharmacology 20190106 6

<h4>Rationale</h4>Stressful life events are suggested to contribute to the development of various pathologies, such as cardiovascular disorders, whose etiopathogenesis is highly associated with elevated levels of serum amyloid A (SAA) proteins. SAA synthesis in the liver is regulated by a complex network of cytokines acting independently or in concert with various hormones/stimulants including the stress-activated sympathetic nervous system.<h4>Objective</h4>This study aims to investigate the un ...[more]

PMID: 30612190

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Project description:Microglial cells are resident immune cells of the central nervous system (CNS), recognized as key elements in the regulation of neural homeostasis and the response to injury and repair. As excessive activation of microglia may lead to neurodegeneration, therapeutic strategies targeting its inhibition were shown to improve treatment of most neurodegenerative diseases. Benfotiamine is a synthetic vitamin B1 (thiamine) derivate exerting potentially anti-inflammatory effects. Despite the encouraging results regarding benfotiamine potential to alleviate diabetic microangiopathy, neuropathy and other oxidative stress-induced pathological conditions, its activities and cellular mechanisms during microglial activation have yet to be elucidated. In the present study, the anti-inflammatory effects of benfotiamine were investigated in lipopolysaccharide (LPS)-stimulated murine BV-2 microglia. We determined that benfotiamine remodels activated microglia to acquire the shape that is characteristic of non-stimulated BV-2 cells. In addition, benfotiamine significantly decreased production of pro-inflammatory mediators such as inducible form of nitric oxide synthase (iNOS) and NO; cyclooxygenase-2 (COX-2), heat-shock protein 70 (Hsp70), tumor necrosis factor alpha ? (TNF-?), interleukin-6 (IL-6), whereas it increased anti-inflammatory interleukin-10 (IL-10) production in LPS stimulated BV-2 microglia. Moreover, benfotiamine suppressed the phosphorylation of extracellular signal-regulated kinases 1/2 (ERK1/2), c-Jun N-terminal kinases (JNK) and protein kinase B Akt/PKB. Treatment with specific inhibitors revealed that benfotiamine-mediated suppression of NO production was via JNK1/2 and Akt pathway, while the cytokine suppression includes ERK1/2, JNK1/2 and Akt pathways. Finally, the potentially protective effect is mediated by the suppression of translocation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-?B) in the nucleus. Therefore, benfotiamine may have therapeutic potential for neurodegenerative diseases by inhibiting inflammatory mediators and enhancing anti-inflammatory factor production in activated microglia.

Project description:Background and purposeWhile maintaining cardiac performance, chronic ?-adrenoceptor activation eventually exacerbates the progression of cardiac remodelling and failure. We examined the adverse signalling pathways mediated by nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and reactive oxygen species (ROS) after chronic ??-adrenoceptor activation.Experimental approachMice with transgenic ??-adrenoceptor overexpression (??-TG) and non-transgenic littermates were either untreated or treated with an antioxidant (N-acetylcysteine, NAC) or NADPH oxidase inhibitors (apocynin, diphenyliodonium). Levels of ROS, phosphorylated p38 mitogen-activated protein kinase (MAPK), pro-inflammatory cytokines and collagen content in the left ventricle (LV) and LV function were measured and compared.Key results??-TG mice showed increased ROS production, phosphorylation of p38 MAPK and heat shock protein 27 (HSP27), expression of pro-inflammatory cytokines and collagen, and progressive ventricular dysfunction. ??-adrenoceptor stimulation similarly increased ROS production and phosphorylation of p38 MAPK and HSP27 in cultured cardiomyocytes. Treatment with apocynin, diphenyliodonium or NAC reduced phosphorylation of p38 MAPK and HSP27 in both cultured cardiomyocytes and the LV of ??-TG mice. NAC treatment (500 mg·kg?¹ ·day?¹) for 2 weeks eliminated the up-regulated expression of pro-inflammatory cytokines and collagen in the LV of ??-TG mice. Chronic NAC treatment to ??-TG mice from 7 to 10 months of age largely prevented progression of ventricular dilatation, preserved contractile function (fractional shortening 37 ± 5% vs. 25 ± 3%, ejection fraction 52 ± 5% vs. 32 ± 4%, both P < 0.05), reduced cardiac fibrosis and suppressed matrix metalloproteinase activity.Conclusion and implications??-adrenoceptor stimulation provoked NADPH oxidase-derived ROS production in the heart. Elevated ROS activated p38 MAPK and contributed significantly to cardiac inflammation, remodelling and failure.

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Adrenoceptor-stimulated inflammatory response in stress-induced serum amyloid A synthesis.

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Adrenoceptor-stimulated inflammatory response in stress-induced serum amyloid A synthesis.

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