Objective(s): We aimed to show that the immune system is sensitive to the detrimental effects of inequality and social injustice, and splenic vulnerability to apoptosis may also increase. Methods: In order of better determination of immune responses to chronic social stress, we implemented food deprivation, food intake inequality, and unstable social status (a change of cage-mate every 3 days) for a period of 14 days in 60 male Balb/c mice. At the end of this stress period, nitric oxide (NO) production by peritoneal adherent cells and the serum concentration of corticosterone were measured. Moreover, the viability of peritoneal adherent cells and spleen lymphocytes was evaluated by MTT assay. The terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assay was done to reveal the TUNEL-reactive apoptotic bodies in the spleen. Results: Our results showed that food deprivation and inequality caused significant changes in the apoptosis of splenic cells in comparison with the control group (p < 0.05). Moreover, the vital activities of lymphocytes and peritoneal adherent cells, as well as NO production by the latter, increased significantly (p < 0.05). However, the experience of unstable social status did not cause a further increase in the viability of lymphocytes and peritoneal adherent cells, or NO production in animals that were food-deprived or experienced inequality. Serum concentration of corticosterone in all experimental groups, except for animals that experienced unstable social status only, significantly decreased versus the control group (p < 0.05). Conclusions: The results suggest that poverty and social inequality, but not unstable social status, affect immune responses and are likely involved in the induction of splenic apoptosis in mice.

Keywords:
Food deprivation, Social inequality, Unstable social status, Nitric oxide, Apoptosis, Macrophages, Lymphocyte viability
1.
Murali V, Oyebode F: Poverty, social inequality and mental health. Adv Psychiatr Treat 2004;10:216-224.
2.
Narayan-Parker D, Patel R: Can Anyone Hear Us? (Voices of the Poor, vol 1). New York, World Bank Publications, 2000.
3.
Books S: Poverty and Schooling in the US: Contexts and Consequences, ed 1. Mahwah, Lawrence Erlbaum, 2004.
4.
Marmot M: Social determinants of health inequalities. Lancet 2005;365:1099-1104.
5.
Braveman PA, Egerter SA, Mockenhaupt RE: Broadening the focus: the need to address the social determinants of health. Am J Prev Med 2011;40:S4-S18.
6.
Farrell C, McAvoy H, Wilde J: Tackling health inequalities. An all-Ireland approach to social determinants. Institute of Public Health in Ireland/Combat Poverty Agency, 2008.
7.
Aghajani M, Mahdavi MRV, Najafabadi MK, Ghazanfari T, Azimi A, Soleymani SA, Dust SM: Effects of dominant/subordinate social status on formalin-induced pain and changes in serum proinflammatory cytokine concentrations in mice. PLoS One 2013;8:e80650.
8.
Aghajani M, Mahdavi V, Reza M, Ghazanfari T, Khalili M, Azimi A, Arbab Soleymani S: Effects of dominant/subordinate social status on pain behavior and proinflammatory cytokines in the serum of mice. Physiol Pharmacol 2013;16:380-392.
9.
Kim P, Evans GW, Angstadt M, Ho SS, Sripada CS, Swain JE, Liberzon I, Phan KL: Effects of childhood poverty and chronic stress on emotion regulatory brain function in adulthood. PNAS 2013;110:18442-18447.
10.
Dhabhar FS: Enhancing versus suppressive effects of stress on immune function: implications for immunoprotection versus immunopathology. Allergy Asthma Clin Immunol 2008;4:2-11.
11.
O'Leary A: Stress, emotion, and human immune function. Psychol Bull 1990;108:363-382.
12.
Segerstrom SC, Miller GE: Psychological stress and the human immune system: a meta-analytic study of 30 years of inquiry. Psychol Bull 2004;130:601-630.
13.
West DA, Leung GM, Jiang CQ, Elwell-Sutton TM, Zhang WS, Lam TH, Cheng KK, Schooling CM: Life-course origins of social inequalities in adult immune cell markers of inflammation in a developing southern Chinese population: the Guangzhou Biobank Cohort Study. BMC Public Health 2012;12:269.
14.
Trueba AF, Rosenfield D, Smith NB, Gorena TL, Ritz T: Social support as a predictor exhaled nitric oxide in healthy individuals across time. Int J Psychophysiol 2014;93:356-362.
15.
Wink DA, Hines HB, Cheng RY, Switzer CH, Flores-Santana W, Vitek MP, Ridnour LA, Colton CA: Nitric oxide and redox mechanisms in the immune response. J Leukoc Biol 2011;89:873-891.
16.
Esch T, Stefano GB, Fricchione GL, Benson H: Stress-related diseases - a potential role for nitric oxide. Med Sci Monit 2002;8:RA103-RA118.
17.
Gutierrez FR, Mineo TW, Pavanelli WR, Guedes PM, Silva JSL: The effects of nitric oxide on the immune system during Trypanosoma cruzi infection. Mem Inst Oswaldo Cruz 2009;104:236-245.
18.
Livonesi MC, Rossi MA, de Souto JT, Campanelli AP, de Sousa RLM, Maffei CML, Ferreira BR, Martinez R, da Silva JS: Inducible nitric oxide synthase-deficient mice show exacerbated inflammatory process and high production of both Th1 and Th2 cytokines during paracoccidioidomycosis. Microbes Infect 2009;11:123-132.
19.
Wei T, Chen C, Hou J, Xin W, Mori A: Nitric oxide induces oxidative stress and apoptosis in neuronal cells. Biochim Biophys Acta 2000;1498:72-79.
20.
Hernandez LM, Blazer DG (eds): Genes, Behavior, and the Social Environment: Moving Beyond the Nature/Nurture Debate. Washington DC, National Academies Press, 2006.
21.
Heidary F, Mahdavi MRV, Momeni F, Minaii B, Rogani M, Fallah N, Heidary R, Gharebaghi R: Food inequality negatively impacts cardiac health in rabbits. PLoS One 2008;3:e3705.
22.
Mojarab S, Mahdavi MRV, Roghani M, Safarpour AR, Tiraihi T, Faghihzadeh S, Azathy MH, Nasabi NA: Effect of food inequality and unstable social status on myocardial cells of male rabbits. World Appl Sci 2010;8:680-686.
23.
Rowland NE: Food or fluid restriction in common laboratory animals: balancing welfare considerations with scientific inquiry. Comp Med 2007;57:149-160.
24.
Silasi G, Hamilton DA, Kolb B: Social instability blocks functional restitution following motor cortex stroke in rats. Behav Brain Res 2008;188:219-226.
25.
Hargraves WA, Hentall ID: Analgesic effects of dietary caloric restriction in adult mice. Pain 2005;114:455-461.
26.
Royo F, Bjork N, Carlsson H, Mayo S, Hau J: Impact of chronic catheterization and automated blood sampling (Accusampler) on serum corticosterone and fecal immunoreactive corticosterone metabolites and immunoglobulin A in male rats. J Endocrinol 2004;180:145-153.
27.
Potter M: History of the BALB/c family. Curr Top Microbiol Immunol 1985;122:1-5.
28.
Yaraee R, Ghazanfari T, Eghtedardoost M, Rajabi M, Naseri M: The effect of MS14 on innate and cellular immune responses in BALB/c mice. Immunopharmacol Immunotoxicol 2011;33:509-514.
29.
Moradi F, Mahdavi V, Reza M, Ahmadiani A, Rogani M, Altiraihi T, Mojarab S: Can social instability, food deprivation and food inequality accelerate neuronal aging? BCN 2012;3:38-48.
30.
Matsuda N, Teramae H, Futatsugi M, Takano K-i, Yamamoto S, Tomita K, Suzuki T, Yokoo H, Koike K, Hattori Y: Up-regulation of histamine H4 receptors contributes to splenic apoptosis in septic mice: counteraction of the antiapoptotic action of nuclear factor-κB. J Pharmacol Exp Ther 2010;332:730-737.
31.
Aghajani M, Faghihi M, Imani A, Vaez Mahdavi MR, Shakoori A, Rastegar T, Parsa H, Mehrabi S, Moradi F, Kazemi Moghaddam E: Post-infarct sleep disruption and its relation to cardiac remodeling in a rat model of myocardial infarction. Chronobiol Int 2017;34:587-600.
32.
Yin D, Tuthill D, Mufson RA, Shi Y: Chronic restraint stress promotes lymphocyte apoptosis by modulating CD95 expression. J Exp Med 2000;191:1423-1428.
33.
Aghajani M, Mahdavi V, Reza M, Ghazanfari T, Khalili M, Azimi A, Arbab Soleymani S, Mahdi Dust S: Effects of social stress on pain behavior, immune cells and serum concentrations of TNF-α, interleukin-1 and interleukin-6 in female mice. Physiol Pharmacol 2012;15:545-561.
34.
Sorensen M, Sanz A, Gomez J, Pamplona R, Portero-Otin M, Gredilla R, Barja G: Effects of fasting on oxidative stress in rat liver mitochondria. Free Radic Res 2006;40:339-347.
35.
Zhao J: Interplay among nitric oxide and reactive oxygen species: a complex network determining cell survival or death. Plant Signal Behav 2007;2:544-547.
36.
Elmore S: Apoptosis: a review of programmed cell death. Toxicol Pathol 2007;35:495-516.
37.
Shi Y, Devadas S, Greeneltch KM, Yin D, Mufson RA, Zhou J-N: Stressed to death: implication of lymphocyte apoptosis for psychoneuroimmunology. Brain Behav Immun 2003;17:18-26.
38.
Yin D, Mufson RA, Wang R, Shi Y: Fas-mediated cell death promoted by opioids. Nature 1999;397:218.
39.
Zhang Y, Zhang Y, Miao J, Hanley G, Stuart C, Sun X, Chen T, Yin D: Chronic restraint stress promotes immune suppression through toll-like receptor 4-mediated phosphoinositide 3-kinase signaling. J Neuroimmunol 2008;204:13-19.
40.
Domínguez-Gerpe L, Rey-Méndez M: Alterations induced by chronic stress in lymphocyte subsets of blood and primary and secondary immune organs of mice. BMC Immunol 2001;2:7.
41.
Spiers JG, Chen H-JC, Sernia C, Lavidis NA: Activation of the hypothalamic-pituitary-adrenal stress axis induces cellular oxidative stress. Front Neurosci 2014;8:456.
42.
Wronska-Fortuna D, Sechman A, Niezgoda J, Bobek S: Modified responses of circulating cortisol, thyroid hormones, and glucose to exogenous corticotropin and thyrotropin-releasing hormone in food-deprived sheep. Pharmacol Biochem Behav 1993;45:601-606.
43.
Chu Y, Mouat M, Harris R, Coffield J, Grider A: Water maze performance and changes in serum corticosterone levels in zinc-deprived and pair-fed rats. Physiol Behav 2003;78:569-578.
44.
Mahdi Dust S, Mahdavi V, Reza M, Kabudanian Ardestani S, Sedaghat R, Jalilvand F, Khalili M, Aghajani M, Azimi A: Effect of stress due to food deprivation, social inequality and instability on brain lipofuscin levels. Physiol Pharmacol 2013;16:350-359.
45.
McEwen BS: Protection and damage from acute and chronic stress: allostasis and allostatic overload and relevance to the pathophysiology of psychiatric disorders. Ann NY Acad Sci 2004;1032:1-7.
46.
Dhabhar FS: Stress-induced enhancement of cell-mediated immunity. Ann NY Acad Sci 1998;840:359-372.
47.
Spencer RL, Miller A, Moday H, McEwen B, Blanchard R, Blanchard D, Sakai R: Chronic social stress produces reductions in available splenic type II corticosteroid receptor binding and plasma corticosteroid binding globulin levels. Psychoneuroendocrinology 1996;21:95-109.
48.
Xiang Y, Yan H, Zhou J, Zhang Q, Hanley G, Caudle Y, LeSage G, Zhang X, Yin D: The role of toll-like receptor 9 in chronic stress-induced apoptosis in macrophage. PLoS One 2015;10:e0123447.
49.
Gleeson M, Bishop N: Special feature for the Olympics: effects of exercise on the immune system: modification of immune responses to exercise by carbohydrate, glutamine and anti-oxidant supplements. Immunol Cell Biol 2000;78:554-561.
50.
Snyder CM, Shroff EH, Liu J, Chandel NS: Nitric oxide induces cell death by regulating anti-apoptotic BCL-2 family members. PLoS One 2009;4:e7059.
© 2017 S. Karger AG, Basel
2017
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.