Stress is an important risk factors for human diseases. It activates the hypothalamic-pituitary-adrenal (HPA) axis and increases plasma glucocorticoids, which are powerful regulators of immune system. The response of the target cells to glucocorticoids depends not only on the plasma concentrations of cortisol and corticosterone but also on their local metabolism. This metabolism is catalyzed by 11β-hydroxysteroid dehydrogenases type 1 and 2, which interconvert glucocorticoid hormones cortisol and corticosterone and their 11-oxo metabolites cortisone and 11-dehydrocorticosterone. The goal of this study was to determine whether stress modulates glucocorticoid metabolism within lymphoid organs - the structures where immune cells undergo development and activation. Using the resident-intruder paradigm, we studied the effect of social stress on glucocorticoid metabolism in primary and secondary lymphoid organs of Fisher 344 (F344) and Lewis (LEW) rats, which exhibit marked differences in their HPA axis response to social stressors and inflammation. We show that repeated social defeat increased the regeneration of corticosterone from 11-dehydrocorticosterone in the thymus, spleen and mesenteric lymphatic nodes (MLN). Compared with the F344 strain, LEW rats showed higher corticosterone regeneration in splenocytes of unstressed rats and in thymic and MLN mobile cells after stress but corticosterone regeneration in the stroma of all lymphoid organs was similar in both strains. Inactivation of corticosterone to 11-dehydrocorticosterone was found only in the stroma of lymphoid organs but not in mobile lymphoid cells and was not upregulated by stress. Together, our findings demonstrate the tissue- and strain-dependent regeneration of glucocorticoids following social stress.

Department of Physiology Faculty of Science Charles University Prague Czech Republic

Institute of Physiology Academy of Sciences of the Czech Republic Prague Czech Republic

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McEwen BS, Biron CA, Brunson KW, Bulloch K, Chambers WH, Dhabhar FS, Goldfarb RH, Kitson RP, Miller AH, Spencer RL, et al The role of adrenocorticoids as modulators of immune function in health and disease: neural, endocrine and immune interactions. Brain Research Reviews 1997. 23 79–133. (10.1016/S0165-0173(96)00012-4) PubMed DOI

Cohen S, Janicki-Deverts D, Doyle WJ, Miller GE, Frank E, Rabin BS, Turner RB. Chronic stress, glucocorticoid receptor resistance, inflammation, and disease risk. PNAS 2012. 109 5995–5999. (10.1073/pnas.1118355109) PubMed DOI PMC

Silverman MN, Sternberg EM. Glucocorticoid regulation of inflammation and its functional correlates: from HPA axis to glucocorticoid receptor dysfunction. Annals of the New York Academy of Sciences 2012. 1261 55–63. (10.1111/j.1749-6632.2012.06633.x) PubMed DOI PMC

Bowers SL, Bilbo SD, Dhabhar FS, Nelson RJ. Stressor-specific alterations in corticosterone and immune responses in mice. Brain Behavior and Immunity 2008. 22 105–113. (10.1016/j.bbi.2007.07.012) PubMed DOI PMC

Chapman K, Holmes M, Seckl J. 11β-Hydroxysteroid dehydrogenases: intracellular gate-keepers of tissue glucocorticoid action. Physiological Reviews 2013. 93 1139–1206. (10.1152/physrev.00020.2012) PubMed DOI PMC

Ergang P, Vytáčková K, Švec J, Bryndová J, Mikšík I, Pácha J. Upregulation of 11β-hydroxysteroid dehydrogenase 1 in lymphoid organs during inflammation in the rat. Journal of Steroid Biochemistry and Molecular Biology 2011. 126 19–25. (10.1016/j.jsbmb.2011.04.002) PubMed DOI

Nuotio-Antar AM, Hasty AH, Kovacs WJ. Quantitation and cellular localization of 11β-HSD1 expression in murine thymus. Journal of Steroid Biochemistry and Molecular Biology 2006. 99 93–99. (10.1016/j.jsbmb.2006.01.011) PubMed DOI

Taves MD, Plumb AW, Korol AM, Van Der Gugten JG, Holmes DT, Abraham N, Soma KK. Lymphoid organs of neonatal and adult mice preferentially produce active glucocorticoids from metabolites, not precursors. Brain Behavior and Immunity 2016. 57 271–281. (10.1016/j.bbi.2016.05.003) PubMed DOI

Zhang TY, Ding X, Daynes RA. The expression of 11β-hydroxysteroid dehydrogenase type I by lymphocytes provides a novel means for intracrine regulation of glucocorticoid activities. Journal of Immunology 2005. 174 879–889. (10.4049/jimmunol.174.2.879) PubMed DOI

Hennebold JD, Ryu SY, Mu HH, Galbraith A, Daynes RA. 11β-Hydroxysteroid dehydrogenase modulation of glucocorticoid activities in lymphoid organs. American Journal of Physiology: Regulatory, Integrative and Comparative Physiology 1996. 270 R1296–R1306. (10.1152/ajpregu.1996.270.6.R1296) PubMed DOI

Corona-Pérez A, Díaz-Muñoz M, Rodríguez IS, Cuevas E, Martínez-Gómez M, Castelán F, Rodríguez-Antolín J, Nicolás-Toledo L. High sucrose intake ameliorates the accumulation of hepatic triacylglycerol promoted by restraint stress in young rats. Lipids 2015. 50 1103–1113. PubMed

Ergang P, Vodička M, Soták M, Klusoňová P, Behuliak M, Řeháková L, Zach P, Pácha J. Differential impact of stress on hypothalamic-pituitary-adrenal axis: gene expression changes in Lewis and Fisher rats. Psychoneuroendocrinology 2015. 53 49–59. (10.1016/j.psyneuen.2014.12.013) PubMed DOI

Jamieson PM, Fuchs E, Flugge G, Seckl JR. Attenuation of hippocampal 11β-hydroxysteroid dehydrogenase type 1 by chronic psychosocial stress in the tree shrew. Stress 1997. 2 123–132. (10.3109/10253899709014743) PubMed DOI

Jellinck PH, Dhabhar FS, Sakai RR, McEwen BS. Long-term corticosteroid treatment but not chronic stress affects 11β-hydroxysteroid dehydrogenase type I activity in rat brain and peripheral tissues. Journal of Steroid Biochemistry and Molecular Biology 1997. 60 319–323. (10.1016/S0960-0760(96)00197-5) PubMed DOI

Monder C, Sakai RR, Miroff Y, Blanchard DC, Blanchard RJ. Reciprocal changes in plasma corticosterone and testosterone in stressed male rats maintained in a visible burrow system: evidence for a mediating role of testicular 11β-hydroxysteroid dehydrogenase. Endocrinology 1994. 134 1193–1198. (10.1210/endo.134.3.8119159) PubMed DOI

Sesti-Costa R, Ignacchiti MD, Chedraoui-Silva S, Marchi LF, Mantovani B. Chronic cold stress in mice induces a regulatory phenotype in macrophages: correlation with increased 11β-hydroxysteroid dehydrogenase expression. Brain Behavior and Immunity 2012. 26 50–60. (10.1016/j.bbi.2011.07.234) PubMed DOI

Reber SO, Peters S, Slattery DA, Hofmann C, Schölmerich J, Neumann ID, Obermeier F. Mucosal immunosuppression and epithelial barrier defects are key events in murine psychosocial stress-induced colitis. Brain Behavior and Immunity 2011. 25 1153–1161. (10.1016/j.bbi.2011.03.004) PubMed DOI

Cohen S, Janicki-Deverts D, Miller GE. Psychological stress and disease. JAMA 2007. 298 1685–1687. (10.1001/jama.298.14.1685) PubMed DOI

Ashwell JD, Lu FW, Vacchio MS. Glucocorticoids in T cell development and function. Annul Review of Immunology 2000. 18 309–345. (10.1146/annurev.immunol.18.1.309) PubMed DOI

Tuckermann JP, Kleiman A, Moriggl R, Spanbroek R, Neumann A, Illing A, Clausen BE, Stride B, Förster I, Habenicht AJ, et al Macrophages and neutrophils are the targets for immune suppression by glucocorticoids in contact allergy. Journal of Clinical Investigation 2007. 117 1381–1390. (10.1172/JCI28034) PubMed DOI PMC

Mittelstadt PR, Monteiro JP, Ashwell JD. Thymocyte responsiveness to endogenous glucocorticoids is required for immunological fitness. Journal of Clinical Investigation 2012. 122 2384–2394. (10.1172/JCI63067) PubMed DOI PMC

Dhabhar FS, Miller AH, McEwen BS, Spencer RL. Differential activation of adrenal steroid receptors in neural and immune tissues of Sprague Dawley, Fischer 344, and Lewis rats. Journal of Neuroimmunology 1995. 56 77–90. (10.1016/0165-5728(94)00135-B) PubMed DOI

Dhabhar FS, McEwen BS, Spencer RL. Adaptation to prolonged or repeated stress – comparison between rat strains showing intrinsic differences in reactivity to acute stress. Neuroendocrinology 1997. 65 360–368. (10.1159/000127196) PubMed DOI

Sternberg EM, Hill JM, Chrousos GP, Kamilaris T, Listwak SJ, Gold PW, Wilder RL. Inflammatory mediator-induced hypothalamic-pituitary-adrenal axis activation is defective in streptococcal cell wall arthritis-susceptible Lewis rats. PNAS 1989. 86 2374–2378. (10.1073/pnas.86.7.2374) PubMed DOI PMC

Chaouloff F. Social stress models in depression research: what do they tell us? Cell and Tissue Research 2013. 354 179–190. (10.1007/s00441-013-1606-x) PubMed DOI PMC

Buwalda B, Kole MH, Veenema AH, Huininga M, de Boer SF, Korte SM, Koolhaas JM. Long-term effects of social stress on brain and behavior: a focus on hippocampal functioning. Neuroscience and Biobehavioral Reviews 2005. 29 83–97. (10.1016/j.neubiorev.2004.05.005) PubMed DOI

Haller J, Fuchs E, Halász J, Makara GB. Defeat is a major stressor in males while social instability is stressful mainly in females: towards the development of a social stress model in female rats. Brain Research Bulletin 1999. 50 33–39. (10.1016/S0361-9230(99)00087-8) PubMed DOI

Pácha J, Mikšík I, Lisá V, Pohlová I. Hormonal regulation of intestinal 11β-hydroxysteroid dehydrogenase. Life Sciences 1997. 61 2391–2396. (10.1016/S0024-3205(97)00956-9) PubMed DOI

Pácha J, Mikšík I, Mrnka L, Zemanová Z, Bryndová J, Mazancová K, Kučka M. Corticosteroid regulation of colonic ion transport during postnatal development: methods for corticosteroid analysis. Physiological Research 2004. 53 S63–S80. PubMed

Keller-Wood M. Hypothalamic-pituitary-adrenal axis-feedback control. Comprehensive Physiology 2015. 53 1161–1182. (10.1002/cphy.c140065) PubMed DOI

Almanzar G, Mayerl C, Seitz JC, Höfner K, Brunner A, Wild V, Jahn D, Geier A, Fassnacht M, Prelog M. Expression of 11β-hydroxysteroid-dehydrogenase type 2 in human thymus. Steroids 2016. 110 35–40. (10.1016/j.steroids.2016.03.019) PubMed DOI

Qiao S, Chen L, Okret S, Jondal M. Age-related synthesis of glucocorticoids in thymocytes. Experimental Cell Research 2008. 314 3027–3035. (10.1016/j.yexcr.2008.06.014) PubMed DOI

Esteves CL, Kelly V, Breton A, Taylor AI, West CC, Donadeu FX, Péault B, Seckl JR, Chapman KE. Proinflammatory cytokine induction of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) in human adipocytes is mediated by MEK, C/EBPβ, and NF-κB/RelA. Journal of Clinical Endocrinology and Metabolism 2014. 99 E160–E168. (10.1210/jc.2013-1708) PubMed DOI

Ignatova ID, Kostadinova RM, Goldring CE, Nawrocki AR, Frey FJ, Frey BM. Tumor necrosis factor-α upregulates 11β-hydroxysteroid dehydrogenase type 1 expression by CCAAT/enhancer binding protein-β in HepG2 cells. American Journal of Physiology: Endocrinology and Metabolism 2009. 296 E367–E377. (10.1152/ajpendo.90531.2008) PubMed DOI

Briest W, Rassler B, Deten A, Leicht M, Morwinski R, Neichel D, Wallukat G, Ziegelhöffer T, Zimmer HG. Norepinephrine-induced interleukin-6 increase in rat hearts: differential signal transduction in myocytes and non-myocytes. Pflügers Archiv: Europen Journal of Physiology 2003. 446 437–446. (10.1007/s00424-003-1043-x) PubMed DOI

Cardinaux JR, Magistretti PJ. Vasoactive intestinal peptide, pituitary adenylate cyclase-activating peptide, and noradrenaline induce the transcription factors CCAAT/enhancer binding protein (C/EBP)-β and C/EBP-δ in mouse cortical astrocytes: involvement in cAMP-regulated glycogen metabolism. Journal of Neuroscience 1996. 16 919–929. (10.1523/JNEUROSCI.16-03-00919.1996) PubMed DOI PMC

Sai S, Esteves CL, Kelly V, Michailidou Z, Anderson K, Coll AP, Nakagawa Y, Ohzeki T, Seckl JR, Chapman KE. Glucocorticoid regulation of the promoter of 11β-hydroxysteroid dehydrogenase type 1 is indirect and requires CCAAT/enhancer-binding protein-β. Molecular Endocrinology 2008. 22 2049–2060. (10.1210/me.2007-0489) PubMed DOI PMC

Laukova M, Vargovic P, Vlcek M, Lejavova K, Hudecova S, Krizanova O, Kvetnansky R. Catecholamine production is differently regulated in splenic T- and B-cells following stress exposure. Immunobiology 2013. 218 780–789. (10.1016/j.imbio.2012.08.279) PubMed DOI

Jondal M, Pazirandeh A, Okret S. Different roles for glucocorticoids in thymocyte homeostasis? Trends in Immunology 2004. 25 595–600. (10.1016/j.it.2004.09.003) PubMed DOI

Profiling of adrenal corticosteroids in blood and local tissues of mice during chronic stress