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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-1β, IL-6, and TNFα 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 α1- and β1/2-ARs mimics the stress effect on SAA1/2 regulation, whereas α2-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-1β levels, whereas IL-1β inhibition with Anakinra mimics this sodium salicylate preventive effect, thus indicating a crucial role for IL-1β. Interestingly, the AR-driven SAA3 synthesis was elevated by sodium salicylate in a TNFα-dependent way, supporting diverse and complex regulatory roles of cytokines in SAA production. In contrast to α1/α2-AR, the β1/2-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.

journal_name

Psychopharmacology (Berl)

journal_title

Psychopharmacology

authors

Konstandi M,Sotiropoulos I,Matsubara T,Malliou F,Katsogridaki A,Andriopoulou CE,Gonzalez FJ

doi

10.1007/s00213-018-5149-4

subject

Has Abstract

pub_date

2019-06-01 00:00:00

pages

1687-1699

issue

eissn

0033-3158

issn

1432-2072

pii

10.1007/s00213-018-5149-4

journal_volume

236

pub_type

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