Skip to main content

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

Psychopharmacology volume 236, pages 1687–1699 (2019)Cite this article

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.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

43,34 €

Price includes VAT (Finland)
Tax calculation will be finalised during checkout.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

References

  • Aich P, Potter AA, Griebel PJ (2009) Modern approaches to understanding stress and disease susceptibility: a review with special emphasis on respiratory disease. Int J Gen Med 2:19–32

    Article  PubMed  PubMed Central  Google Scholar 

  • Artl A, Marsche G, Lestavel S, Sattler W, Malle E (2000) Role of serum amyloid A during metabolism of acute-phase HDL by macrophages. Arterioscler Thromb Vasc Biol 20:763–772

    Article  CAS  PubMed  Google Scholar 

  • Barneda-Zahonero B, Minano-Molina A, Badiola N, Fado R, Xifro X, Saura CA, Rodriguez-Alvarez J (2009) Bone morphogenetic protein-6 promotes cerebellar granule neurons survival by activation of the MEK/ERK/CREB pathway. Mol Biol Cell 20:5051–5063

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bryleva EY, Keaton SA, Grit J, Madaj Z, Sauro-Nagendra A, Smart L, Halstead S, Achtyes E, Brundin L (2017) The acute-phase mediator serum amyloid A is associated with symptoms of depression and fatigue. Acta Psychiatr Scand 135:409–418

    Article  CAS  PubMed  Google Scholar 

  • Chrousos GP (2009) Stress and disorders of the stress system. Nat Rev Endocrinol 5:374–381

    Article  CAS  PubMed  Google Scholar 

  • Collier CT, Williams PN, Carroll JA, Welsh THJ, Laurenz JC (2011) Effect of maternal restraint stress during gestation on temporal lipopolysaccharide-induced neuroendocrine and immune responses of progeny. Domest Anim Endocrinol 40:40–50

    Article  CAS  PubMed  Google Scholar 

  • Cooper JR, Bloom FE (1996) The biochemical basis of neuropharmacology, 7th edn. Oxford University Press, New York

    Google Scholar 

  • Cray C, Dickey M, Brewer LB, Arheart KL (2013) Assessement of serum amyloid A levels in the rehabilitation setting in the Florida manatee (Trichechus manatus latirostris). J Zoo Wildl Med 44:911–917

    Article  PubMed  Google Scholar 

  • Cruise JL, Knechtle SJ, Bollinger RR, Kuhn C, Michalopoulos G (1987) Alpha 1-adrenergic effects and liver regeneration. Hepatology 7:1189–1194

    Article  CAS  PubMed  Google Scholar 

  • Delerive P, De Bosscher K, Besnard S, Vanden Berghe W, Peters JM, Gonzalez FJ, Fruchart JC, Tedgui A, Haegeman G, Staels B (1999) Peroxisome proliferator-activated receptor alpha negatively regulates the vascular inflammatory gene response by negative cross-talk with transcription factors NF-kappaB and AP-1. J Biol Chem 274:32048–32054

    Article  CAS  Google Scholar 

  • Dong Z, Wu T, Qin W, An C, Wang Z, Zhang M, Zhang Y, Zhang C, An F (2011) Serum amyloid A directly accelerates the progression of atherosclerosis in apolipoprotein E-deficient mice. Mol Med 17:1357–1364

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Elenkov IJ, Wilder RL, Chrousos GP, Vizi ES (2000) The sympathetic nerve—an integrative interface between two supersystems: the brain and the immune system. Pharmacol Rev 52:595–638

    CAS  PubMed  Google Scholar 

  • Fabbri E, Moon TW (2016) Adrenergic signaling in teleost fish liver, a challenging path. Comp Biochem Physiol B Biochem Mol Biol 199:74–86

    Article  CAS  PubMed  Google Scholar 

  • Fasshauer M, Klein J, Kralisch S, Klier M, Lossner U, Bluher M, Paschke R (2004) Serum amyloid A3 expression is stimulated by dexamethasone and interleukin-6 in 3T3-L1 adipocytes. J Endocrinol 183:561–567

    Article  CAS  PubMed  Google Scholar 

  • Flierl MA, Rittirsch D, Nadeau BA, Chen AJ, Sarma JV, Zetoune FS, McGuire SR, List RP, Day DE, Hoesel LM, Gao H, Van Rooijen N, Huber-Lang MS, Neubig RR, Ward PA (2007) Phagocyte-derived catecholamines enhance acute inflammatory injury. Nature 449:721–725

    Article  CAS  PubMed  Google Scholar 

  • Flierl MA, Rittirsch D, Huber-Lang M, Sarma JV, Ward PA (2008) Catecholamines-crafty weapons in the inflammatory arsenal of immune/inflammatory cells or opening pandora’s box? Mol Med 14:195–204

    Article  CAS  PubMed  Google Scholar 

  • Flierl MA, Rittirsch D, Nadeau BA, Sarma JV, Day DE, Lentsch AB, Huber-Lang MS, Ward PA (2009) Upregulation of phagocyte-derived catecholamines augments the acute inflammatory response. PLoS One 4:e4414

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Furchgott RF (1972) The classification of adrenoceptors (adrenergic receptors). An evaluation from the standpoint of receptor theory. In: Blaschko H, Muecholl E (eds) Catecholamines. Springer-Verlag, New York, p 283–335

  • Gabay C, Kushner I (1999) Acute-phase proteins and other systemic responses to inflammation. N Engl J Med 340:448–454

    Article  CAS  PubMed  Google Scholar 

  • Gervois P, Kleemann R, Pilon A, Percevault F, Koenig W, Staels B, Kooistra T (2004) Global suppression of IL-6-induced acute phase response gene expression after chronic in vivo treatment with the peroxisome proliferator-activated receptor-alpha activator fenofibrate. J Biol Chem 279:16154–16160

    Article  CAS  PubMed  Google Scholar 

  • Ghezzi P, Sipe JD (1988) Dexamethasone modulation of LPS, IL-1, and TNF stimulated serum amyloid a synthesis in mice. Lymphokine Res 7:157–166

    CAS  PubMed  Google Scholar 

  • Housby JN, Cahill CM, Chu B, Prevelige R, Bickford K, Stevenson MA, Calderwood SK (1999) Non-steroidal anti-inflammatory drugs inhibit the expression of cytokines and induce HSP70 in human monocytes. Cytokine 11:347–358

    Article  CAS  PubMed  Google Scholar 

  • Husebekk A, Skogen B, Husby G, Marhaug G (1985) Transformation of amyloid precursor SAA to protein AA and incorporation in amyloid fibrils in vivo. Scand J Immunol 21:283–287

    Article  CAS  PubMed  Google Scholar 

  • Jacobsen S, Andersen PH (2007) The acute phase protein serum amyloid A (SAA) as a marker of inflammation in horses. Equine Vet Educ 19:38–46

    Article  Google Scholar 

  • Jayaraman S, Gantz DL, Haupt C, Gursky O (2017) Serum amyloid A forms stable oligomers that disrupt vesicles at lysosomal pH and contribute to the pathogenesis of reactive amyloidosis. Proc Natl Acad Sci U S A 114:E6507–E6515

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Johnson EO, Kamilaris TC, Chrousos GP, Gold PW (1992) Mechanisms of stress: a dynamic overview of hormonal and behavioral homeostasis. Neurosci Biobehav Rev 16:115–130

    Article  CAS  PubMed  Google Scholar 

  • Johnson BD, Kip KE, Marroquin OC, Ridker PM, Kelsey SF, Shaw LJ, Pepine CJ, Sharaf B, Bairey Merz CN, Sopko G, Olson MB, Reis SE (2004) Serum amyloid A as a predictor of coronary artery disease and cardiovascular outcome in women: the National Heart, Lung, and Blood Institute-sponsored Women’s Ischemia Syndrome Evaluation (WISE). Circulation 109:726–732

    Article  CAS  PubMed  Google Scholar 

  • Johnson JD, Campisi J, Sharkey CM, Kennedy SL, Nickerson M, Greenwood BN, Fleshner M (2005) Catecholamines mediate stress-induced increases in peripheral and central inflammatory cytokines. Neuroscience 135:1295–1307

    Article  CAS  PubMed  Google Scholar 

  • Kingman A, Pereira NL (2001) Cardiac amyloidosis. J S C Med Assoc 97:201–206

    CAS  PubMed  Google Scholar 

  • Kisilevsky R (1983) Amyloidosis: a familiar problem in the light of current pathogenetic developments. Lab Investig 49:381–390

    CAS  PubMed  Google Scholar 

  • Konstandi M, Johnson EO, Marselos M, Kostakis D, Fotopoulos A, Lang MA (2004) Stress-mediated modulation of B(alpha)P-induced hepatic CYP1A1: role of catecholamines. Chem Biol Interact 147:65–77

    Article  CAS  PubMed  Google Scholar 

  • Lalchandani SG, Zhang X, Hong SS, Liggett SB, Li W, Moore BM 2nd, Miller DD, Feller DR (2004) Medetomidine analogs as selective agonists for the human alpha2-adrenoceptors. Biochem Pharmacol 67:87–96

    Article  CAS  PubMed  Google Scholar 

  • Langer SZ (2015) Alpha2-adrenoceptors in the treatment of major neuropsychiatric disorders. Trends Pharmacol Sci 36:196–202

    Article  CAS  PubMed  Google Scholar 

  • Lee HJ, Kim JH, Kim SW, Joo HA, Lee HW, Kim YS, Park SJ, Hong SP, Kim TI, Kim WH, Kim YH, Cheon JH (2017) Proteomic analysis of serum amyloid A as a potential marker in intestinal Behcet’s disease. Dig Dis Sci 62:1953–1962

    Article  CAS  PubMed  Google Scholar 

  • Lohse MJ (2015) The ins and outs of adrenergic signaling. J Mol Med (Berl) 93:955–962

    Article  CAS  Google Scholar 

  • Lu J, Liang J, Wang JR, Hu L, Tu Y, Guo JY (2013) Acupuncture activates ERK-CREB pathway in rats exposed to chronic unpredictable mild stress. Evid Based Complement Alternat Med 2013:469765

  • Ma J, Yee A, Brewer HB Jr, Das S, Potter H (1994) Amyloid-associated proteins alpha 1-antichymotrypsin and apolipoprotein E promote assembly of Alzheimer beta-protein into filaments. Nature 372:92–94

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Madden KS, Felten SY, Felten DL, Sundaresan PR, Livnat S (1989) Sympathetic neural modulation of the immune system. I Depression of T cell immunity in vivo and vitro following chemical sympathectomy. Brain Behav Immun 3:72–89

    Article  CAS  PubMed  Google Scholar 

  • Malle E, De Beer FC (1996) Human serum amyloid A (SAA) protein: a prominent acute-phase reactant for clinical practice. Eur J Clin Investig 26:427–435

    Article  CAS  Google Scholar 

  • Marzi C, Huth C, Herder C, Baumert J, Thorand B, Rathmann W, Meisinger C, Wichmann HE, Roden M, Peters A, Grallert H, Koenig W, Illig T (2013) Acute-phase serum amyloid A protein and its implication in the development of type 2 diabetes in the KORA S4/F4 study. Diabetes Care 36:1321–1326

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • McConnell KJ, Olson KL, Delate T, Merenich JA (2009) Factors associated with recurrent coronary events among patients with cardiovascular disease. Pharmacotherapy 29:906–913

    Article  PubMed  Google Scholar 

  • Minneman KP, Esbenshade TA (1994) Alpha 1-adrenergic receptor subtypes. Annu Rev Pharmacol Toxicol 34:117–133

    Article  CAS  PubMed  Google Scholar 

  • Miyazaki Y, Katanasaka Y, Sunagawa Y, Hirano-Sunagawa S, Funamoto M, Morimoto E, Komiyama M, Shimatsu A, Satoh-Asahara N, Yamakage H, Wada H, Hasegawa K, Morimoto T (2016) Effect of statins on atherogenic serum amyloid a and alpha1-antitrypsin low-density lipoprotein complexes. Int J Cardiol 225:332–336

    Article  PubMed  Google Scholar 

  • Nguyen VA, Gao B (1999) Cross-talk between alpha(1B)-adrenergic receptor (alpha(1B)AR) and interleukin-6 (IL-6) signaling pathways. Activation of alpha(1b)AR inhibits il-6-activated STAT3 in hepatic cells by a p42/44 mitogen-activated protein kinase-dependent mechanism. J Biol Chem 274:35492–35498

    Article  CAS  PubMed  Google Scholar 

  • Nicolaides NC, Kyratzi E, Lamprokostopoulou A, Chrousos GP, Charmandari E (2015) Stress, the stress system and the role of glucocorticoids. Neuroimmunomodulation 22:6–19

    Article  CAS  PubMed  Google Scholar 

  • Nishi S, Alchi B, Imai N, Gejyo F (2008) New advances in renal amyloidosis. Clin Exp Nephrol 12:93–101

    Article  CAS  PubMed  Google Scholar 

  • O’Brien KD, McDonald TO, Kunjathoor V, Eng K, Knopp EA, Lewis K, Lopez R, Kirk EA, Chait A, Wight TN, deBeer FC, LeBoeuf RC (2005) Serum amyloid A and lipoprotein retention in murine models of atherosclerosis. Arterioscler Thromb Vasc Biol 25:785–790

    Article  CAS  PubMed  Google Scholar 

  • O’Brien K, Fitzgerald DC, Naiken K, Alugupalli KR, Rostami AM, Gran B (2008) Role of the innate immune system in autoimmune inflammatory demyelination. Curr Med Chem 15:1105–1115

    Article  PubMed  Google Scholar 

  • Pettersson T, Konttinen YT, Maury CP (2008) Treatment strategies for amyloid A amyloidosis. Expert Opin Pharmacother 9:2117–2128

    Article  CAS  PubMed  Google Scholar 

  • Ridker PM, Cushman M, Stampfer MJ, Tracy RP, Hennekens CH (1998) Plasma concentration of C-reactive protein and risk of developing peripheral vascular disease. Circulation 97:425–428

    Article  CAS  PubMed  Google Scholar 

  • Schiller M, Bohm M, Dennler S, Ehrchen JM, Mauviel A (2006) Mitogen- and stress-activated protein kinase 1 is critical for interleukin-1-induced, CREB-mediated, c-fos gene expression in keratinocytes. Oncogene 25:4449–4457

    Article  CAS  PubMed  Google Scholar 

  • Skogen B, Thorsteinsson L, Natvig JB (1980) Degradation of protein SAA to an AA-like fragment by enzymes of monocytic origin. Scand J Immunol 11:533–540

    Article  CAS  PubMed  Google Scholar 

  • Sletten K, Husby G (1974) The complete amino-acid sequence of non-immunoglobulin amyloid fibril protein AS in rheumatoid arthritis. Eur J Biochem 41:117–125

    Article  CAS  PubMed  Google Scholar 

  • Spengler RN, Allen RM, Remick DG, Strieter RM, Kunkel SL (1990) Stimulation of alpha-adrenergic receptor augments the production of macrophage-derived tumor necrosis factor. J Immunol 145:1430–1434

    CAS  PubMed  Google Scholar 

  • Spengler RN, Chensue SW, Giacherio DA, Blenk N, Kunkel SL (1994) Endogenous norepinephrine regulates tumor necrosis factor-alpha production from macrophages in vitro. J Immunol 152:3024–3031

    CAS  PubMed  Google Scholar 

  • Staels B, Koenig W, Habib A, Merval R, Lebret M, Torra IP, Delerive P, Fadel A, Chinetti G, Fruchart JC, Najib J, Maclouf J, Tedgui A (1998) Activation of human aortic smooth-muscle cells is inhibited by PPARalpha but not by PPARgamma activators. Nature 393:790–793

    Article  CAS  Google Scholar 

  • Steel DM, Whitehead AS (1994) The major acute phase reactants: C-reactive protein, serum amyloid P component and serum amyloid a protein. Immunol Today 15:81–88

    Article  CAS  PubMed  Google Scholar 

  • Sternberg EM (2006) Neural regulation of innate immunity: a coordinated nonspecific host response to pathogens. Nat Rev Immunol 6:318–328

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tan KS, Nackley AG, Satterfield K, Maixner W, Diatchenko L, Flood PM (2007) Beta2 adrenergic receptor activation stimulates pro-inflammatory cytokine production in macrophages via PKA- and NF-kappaB-independent mechanisms. Cell Signal 19:251–260

    Article  CAS  PubMed  Google Scholar 

  • Taupin V, Gogusev J, Descampslatscha B, Zavala F (1993) Modulation of tumor-necrosis-factor-alpha, interleukin-1-beta, interleukin-6, interleukin-8, and granulocyte/macrophage colony-stimulating factor expression in human monocytes by an endogenous anxiogenic benzodiazepine ligand, triakontatetraneuropeptide—evidence for a role of prostaglandins. Mol Pharmacol 43:64–69

    CAS  PubMed  Google Scholar 

  • Tracey KJ (2002) The inflammatory reflex. Nature 420:853–859

    Article  CAS  PubMed  Google Scholar 

  • Turlo A, Cywinska A, Czopowicz M, Witkowski L, Niedzwiedz A, Slowikowska M, Borowicz H, Jaskiewicz A, Winnicka A (2015) The effect of different types of musculoskeletal injuries on blood concentration of serum amyloid A in thoroughbred racehorses. PLoS One 10:e0140673

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Uhlar CM, Whitehead AS (1999) Serum amyloid A, the major vertebrate acute-phase reactant. Eur J Biochem 265:501–523

    Article  CAS  PubMed  Google Scholar 

  • Virtanen R (1989) Pharmacological profiles of medetomidine and its antagonist, atipamezole. Acta Vet Scand Suppl 85:29–37

    CAS  PubMed  Google Scholar 

  • Vittimberga FJ Jr, McDade TP, Perugini RA, Callery MP (1999) Sodium salicylate inhibits macrophage TNF-alpha production and alters MAPK activation. J Surg Res 84:143–149

    Article  CAS  PubMed  Google Scholar 

  • Won TW (2013) Fenofibrate, a peroxisome proliferator-activated receptor alpha-agonist, blocks lipopolysaccharide-induced inflammatory pathways in mouse liver. Korean J Hepatobiliary Pancreat Surg 17:89–108

    Article  PubMed  PubMed Central  Google Scholar 

  • Yamazaki K, Kuromitsu J, Tanaka I (2002) Microarray analysis of gene expression changes in mouse liver induced by peroxisome proliferator-activated receptor alpha agonists. Biochem Biophys Res Commun 290:1114–1122

    Article  CAS  PubMed  Google Scholar 

  • Ye RD, Sun L (2015) Emerging functions of serum amyloid A in inflammation. J Leukoc Biol 98:923–929

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang N, Ahsan MH, Purchio AF, West DB (2005) Serum amyloid A-luciferase transgenic mice: response to sepsis, acute arthritis, and contact hypersensitivity and the effects of proteasome inhibition. J Immunol 174:8125–8134

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

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.

Funding

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.

Author information

Affiliations

  1. Faculty of Medicine, Department of Pharmacology, University of Ioannina, Ioannina, Greece

    Maria Konstandi, Foteini Malliou, Alexandra Katsogridaki & Christina E. Andriopoulou

  2. Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

    Maria Konstandi, Tsutomu Matsubara & Frank J. Gonzalez

  3. Life and Health Sciences Research Institute (ICVS), Medical School, University of Minho, Braga, Portugal

    Ioannis Sotiropoulos

  4. ICVS/3B’s - PT Government Associate Laboratory, Braga, Portugal

    Ioannis Sotiropoulos

  5. Graduate School of Medicine, Department of Anatomy and Regenerative Biology, Osaka City University, Osaka, Japan

    Tsutomu Matsubara

Authors
  1. Maria Konstandi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ioannis Sotiropoulos
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Tsutomu Matsubara
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Foteini Malliou
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Alexandra Katsogridaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Christina E. Andriopoulou
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Frank J. Gonzalez
    View author publications

    You can also search for this author in PubMed Google Scholar

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.

Corresponding author

Correspondence to Maria Konstandi.

Ethics declarations

Conflict of interest

The authors declare that they have no conflicts of interest.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

ESM 1

(DOC 63 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Konstandi, M., Sotiropoulos, I., Matsubara, T. et al. Adrenoceptor-stimulated inflammatory response in stress-induced serum amyloid A synthesis. Psychopharmacology 236, 1687–1699 (2019). https://doi.org/10.1007/s00213-018-5149-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-018-5149-4

Keywords

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