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