Please cite this article in press as: A. Wieck, et al., Pro-inflammatory cytokines and soluble receptors in response to acute psychosocial stress: Differential reactivity in bipolar disorder, Neurosci. Lett. (2014), http://dx.doi.org/10.1016/j.neulet.2014.07.040 ARTICLE IN PRESS G Model NSL 30732 1–6 Neuroscience Letters xxx (2014) xxx–xxx Contents lists available at ScienceDirect Neuroscience Letters jo ur nal ho me page: www.elsevier.com/locate/neulet Pro-inflammatory cytokines and soluble receptors in response to acute psychosocial stress: Differential reactivity in bipolar disorder Andrea Wieck a , Rodrigo Grassi-Oliveira a,b , Carine Hartmann do Prado a , Lucas Bortolotto Q1 Rizzo a , Agatha Schommer de Oliveira a , Júlia Kommers-Molina b , Thiago Wendt Viola b , Érica Leandro Marciano Vieira c , Antônio Lúcio Teixeira c , Moisés Evandro Bauer a,d,∗ a Laboratory of Immunosenescence, Institute of Biomedical Research, Pontifical Catholic University of the Rio Grande do Sul (PUCRS), Porto Alegre, Brazil b Cognitive Neuroscience Research Group (GNCD), Centre of Studies and Research in Traumatic Stress (NEPTE), Postgraduate Program in Psychology, PUCRS, Porto Alegre, Brazil c Translational Psychoneuroimmunology Group, School of Medicine, Federal University of Minas Gerais (UFMG), Belo Horizonte, Brazil d PUCRS, Porto Alegre, Brazil h i g h l i g h t s • BD subjects had higher IL-33 and reduced sST2 than controls. • IL-2 increased following stress (TSST), but with lower magnitude in BD. • sTNFR1 decreased following stress (TSST), but with lower magnitude in BD. • BD patients have differential stress reactivity associated with blunted cytokine response to stress. a r t i c l e i n f o Article history: Received 16 June 2014 Received in revised form 15 July 2014 Accepted 24 July 2014 Available online xxx Keywords: Bipolar disorder Psychosocial stress Inflammation Cytokines a b s t r a c t Mounting evidence suggests a chronic pro-inflammatory state in individuals with bipolar disorder (BD). Stress exposure is known to exacerbate several inflammatory conditions as well as psychiatric disorders. Here, we analyzed plasma levels of pro-inflammatory cytokines and their soluble receptors to realistic acute psychosocial stress challenge in BD. Thirteen euthymic type 1 BD patients and 15 matched controls underwent the Trier Social Stress Test protocol (TSST). Blood samples were collected before and after TSST and plasma cytokines interleukin IL-2, IL-6, IL-33, and tumor necrosis factor alpha (TNF-) were measured. In addition TNF- soluble receptors TNFR1 and TNFR2, and IL-33 soluble receptor sST2 were assessed. Increased IL-33 and reduced sST2 levels were observed in BD subjects as compared to controls, independently of stress exposure. Following TSST, there were higher levels of IL-2 and reduced levels of sTNFR1 in both groups. However, the magnitude change for both cytokines was found higher in controls than BD subjects. Our data suggest that BD patients have differential stress reactivity as compared to controls, possibly related to an immunologic imbalance and failure of regulatory mechanisms. © 2014 Published by Elsevier Ireland Ltd. 1. Introduction Chronic low-grade inflammation has been established as one of the mechanisms contributing to the pathophysiology of mood disorders [26]. Indeed, several studies have reported this immune imbalance in participants with bipolar disorders (BD), especially ∗ Corresponding author at: Instituto de Pesquisas Biomédicas, Hospital São Lucas da PUCRS, Av. Ipiranga 6690, 2 ◦ andar, P.O. Box 1429, Porto Alegre, RS 90.610-000, Brazil. Tel.: +55 51 33203000; fax: +55 51 33203312. Q2 E-mail address: mebauer@pucrs.br (M.E. Bauer). associated with a pro-inflammatory profile [28]. Several plasma pro-inflammatory cytokines have been reported increased in BD patients, including IL-2, IL-6, IL-8 and tumor necrosis factor (TNF)-  [20,28]. TNF- is the most studied pro-inflammatory molecule because of its pivotal role in regulating innate immunity, exert- ing its effects by binding two specific receptors, TNFR1 (p55) and TNFR2 (p75) – that can be also found as secreted forms: sTNFR1 and sTNFR2 [14]. The TNFR1 is more abundantly expressed and mediates many actions of TNF-, including activation of transcrip- tion factors, cytokine production and apoptosis in neurons and astrocytes [13]. It has been shown that BD patients had increased plasma levels of sTNFR1 as compared to controls [3]. The TNFR2 http://dx.doi.org/10.1016/j.neulet.2014.07.040 0304-3940/© 2014 Published by Elsevier Ireland Ltd. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49