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

  • Maria KonstandiEmail author
  • Ioannis Sotiropoulos
  • Tsutomu Matsubara
  • Foteini Malliou
  • Alexandra Katsogridaki
  • Christina E. Andriopoulou
  • Frank J. Gonzalez
Original Investigation



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.


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 α12-AR, the β1/2-AR-mediated SAA1/2 and SAA3 upregulation cannot be reversed by fenofibrate, a hypolipidemic drug with anti-inflammatory properties.


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.


SAA1/2 SAA3 Stress Adrenoceptors IL-1β IL-6 TNFα 



The authors would like to thank Dr. Kristopher Krautz for his valuable technical assistance and support and Dr. Konstantinos Ritis, Professor of Immunology, for his constructive comments on these studies.

Author contributions

MK designed the experiments; MK, TM, FM, AK, and CA conducted experiments; MK, IS, and FJG performed data quantification and analysis; MK and IS wrote the manuscript, while FJG was involved in the manuscript revision.


This research was supported by the European Union (European Regional Development Fund- ERDF) and the Greek national funds through the Operational Program “THESSALY- MAINLAND GREECE AND EPIRUS-2007-2013” of the National Strategic Reference Framework (NSRF 2007–2013, Grant 346985/80753) and the National Cancer Institute Intramural Research Program.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflicts of interest.

Supplementary material

213_2018_5149_MOESM1_ESM.doc (63 kb)
ESM 1 (DOC 63 kb)


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Maria Konstandi
    • 1
    • 2
    Email author
  • Ioannis Sotiropoulos
    • 3
    • 4
  • Tsutomu Matsubara
    • 2
    • 5
  • Foteini Malliou
    • 1
  • Alexandra Katsogridaki
    • 1
  • Christina E. Andriopoulou
    • 1
  • Frank J. Gonzalez
    • 2
  1. 1.Faculty of Medicine, Department of PharmacologyUniversity of IoanninaIoanninaGreece
  2. 2.Laboratory of Metabolism, National Cancer InstituteNational Institutes of HealthBethesdaUSA
  3. 3.Life and Health Sciences Research Institute (ICVS)Medical School, University of MinhoBragaPortugal
  4. 4.ICVS/3B’s - PT Government Associate LaboratoryBragaPortugal
  5. 5.Graduate School of Medicine, Department of Anatomy and Regenerative BiologyOsaka City UniversityOsakaJapan

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