Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Glucocorticoid receptor dimerization is required for proper recovery of LPS-induced inflammation, sickness behavior and metabolism in mice

Molecular Psychiatry volume 18, pages 1006–1017 (2013)Cite this article

Subjects

Abstract

Endogenous glucocorticoids are essential for mobilizing energy resources, restraining inflammatory responses and coordinating behavior to an immune challenge. Impaired glucocorticoid receptor (GR) function has been associated with impaired metabolic processes, enhanced inflammation and exaggerated sickness and depressive-like behaviors. To discern the molecular mechanisms underlying GR regulation of physiologic and behavioral responses to a systemic immune challenge, GRdim mice, in which absent GR dimerization leads to impaired GR–DNA-binding-dependent mechanisms but intact GR protein–protein interactions, were administered low-dose lipopolysaccharide (LPS). GRdim-LPS mice exhibited elevated and prolonged levels of plasma corticosterone (CORT), interleukin (IL)-6 and IL-10 (but not plasma tumor necrosis factor-α (TNFα)), enhanced early expression of brain TNFα, IL-1β and IL-6 mRNA levels, and impaired later central TNFα mRNA expression. Exaggerated sickness behavior (lethargy, piloerection, ptosis) in the GRdim-LPS mice was associated with increased early brain proinflammatory cytokine expression and late plasma CORT levels, but decreased late brain TNFα expression. GRdim-LPS mice also exhibited sustained locomotor impairment in the open field, body weight loss and metabolic alterations measured by indirect calorimetry, as well as impaired thermoregulation. Taken together, these data indicate that GR dimerization-dependent DNA-binding mechanisms differentially regulate systemic and central cytokine expression in a cytokine- and time-specific manner, and are essential for the proper regulation and recovery of multiple physiologic responses to low-dose endotoxin. Moreover, these results support the concept that GR protein–protein interactions are not sufficient for glucocorticoids to exert their full anti-inflammatory effects and suggest that glucocorticoid responses limited to GR monomer-mediated transcriptional effects could predispose individuals to prolonged behavioral and metabolic sequelae of an enhanced inflammatory state.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5

Similar content being viewed by others

References

  1. Chrousos GP, Kino T . Glucocorticoid action networks and complex psychiatric and/or somatic disorders. Stress 2007; 10: 213–219.

    Article  CAS  PubMed  Google Scholar 

  2. Sapolsky RM, Romero LM, Munck AU . How do glucocorticoids influence stress responses? Integrating permissive, suppressive, stimulatory, and preparative actions. Endocr Rev 2000; 21: 55–89.

    CAS  PubMed  Google Scholar 

  3. Holsboer F . The corticosteroid receptor hypothesis of depression. Neuropsychopharmacology 2000; 23: 477–501.

    CAS  PubMed  Google Scholar 

  4. McIntyre RS, Soczynska JK, Konarski JZ, Woldeyohannes HO, Law CW, Miranda A et al. Should depressive syndromes be reclassified as “metabolic syndrome type II”? Ann Clin Psychiatry 2007; 19: 257–264.

    Article  PubMed  Google Scholar 

  5. Raison CL, Miller AH . When not enough is too much: the role of insufficient glucocorticoid signaling in the pathophysiology of stress-related disorders. Am J Psychiatry 2003; 160: 1554–1565.

    Article  PubMed  Google Scholar 

  6. Zunszain PA, Anacker C, Cattaneo A, Carvalho LA, Pariante CM . Glucocorticoids cytokines and brain abnormalities in depression. Prog Neuropsychopharmacol Biol Psychiatry 2011; 35: 722–729.

    Article  CAS  PubMed  Google Scholar 

  7. Licinio J, Wong ML . The role of inflammatory mediators in the biology of major depression: central nervous system cytokines modulate the biological substrate of depressive symptoms, regulate stress-responsive systems, and contribute to neurotoxicity and neuroprotection. Mol Psychiatry 1999; 4: 317–327.

    Article  CAS  PubMed  Google Scholar 

  8. Maes M, Yirmyia R, Noraberg J, Brene S, Hibbeln J, Perini G et al. The inflammatory & neurodegenerative (I&ND) hypothesis of depression: leads for future research and new drug developments in depression. Metab Brain Dis 2009; 24: 27–53.

    Article  CAS  PubMed  Google Scholar 

  9. Pollak Y, Yirmiya R . Cytokine-induced changes in mood and behaviour: implications for ‘depression due to a general medical condition’, immunotherapy and antidepressive treatment. Int J Neuropsychopharmacol 2002; 5: 389–399.

    Article  CAS  PubMed  Google Scholar 

  10. Raison CL, Capuron L, Miller AH . Cytokines sing the blues: inflammation and the pathogenesis of depression. Trends Immunol 2006; 27: 24–31.

    Article  CAS  PubMed  Google Scholar 

  11. Dantzer R, O'Connor JC, Freund GG, Johnson RW, Kelley KW . From inflammation to sickness and depression: when the immune system subjugates the brain. Nat Rev Neurosci 2008; 9: 46–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Miller AH, Maletic V, Raison CL . Inflammation and its discontents: the role of cytokines in the pathophysiology of major depression. Biol Psychiatry 2009; 65: 732–741.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Straub RH, Cutolo M, Buttgereit F, Pongratz G . Energy regulation and neuroendocrine-immune control in chronic inflammatory diseases. J Intern Med 2010; 267: 543–560.

    Article  CAS  PubMed  Google Scholar 

  14. Dantzer R . Cytokine-induced sickness behaviour: a neuroimmune response to activation of innate immunity. Eur J Pharmacol 2004; 500: 399–411.

    Article  CAS  PubMed  Google Scholar 

  15. Hart BL . Biological basis of the behavior of sick animals. Neurosci Biobehav Rev 1988; 12: 123–137.

    Article  CAS  PubMed  Google Scholar 

  16. Romanovsky AA, Almeida MC, Aronoff DM, Ivanov AI, Konsman JP, Steiner AA et al. Fever and hypothermia in systemic inflammation: recent discoveries and revisions. Front Biosci 2005; 10: 2193–2216.

    Article  CAS  PubMed  Google Scholar 

  17. Silverman MN, Pearce BD, Biron CA, Miller AH . Immune modulation of the hypothalamic-pituitary-adrenal (HPA) axis during viral infection. Viral Immunol 2005; 18: 41–78.

    Article  CAS  PubMed  Google Scholar 

  18. Hasday JD, Fairchild KD, Shanholtz C . The role of fever in the infected host. Microbes Infect 2000; 2: 1891–1904.

    Article  CAS  PubMed  Google Scholar 

  19. Romanovsky AA, Szekely M . Fever and hypothermia: two adaptive thermoregulatory responses to systemic inflammation. Med Hypotheses 1998; 50: 219–226.

    Article  CAS  PubMed  Google Scholar 

  20. Beisel WR . Metabolic response to infection. Annu Rev Med 1975; 26: 9–20.

    Article  CAS  PubMed  Google Scholar 

  21. Chang HR, Bistrian B . The role of cytokines in the catabolic consequences of infection and injury. JPEN J Parenter Enteral Nutr 1998; 22: 156–166.

    Article  CAS  PubMed  Google Scholar 

  22. Schobitz B, Reul JM, Holsboer F . The role of the hypothalamic-pituitary-adrenocortical system during inflammatory conditions. Crit Rev Neurobiol 1994; 8: 263–291.

    CAS  PubMed  Google Scholar 

  23. Besedovsky HO, del Rey A . Immune-neuro-endocrine interactions: facts and hypotheses. Endocr Rev 1996; 17: 64–102.

    Article  CAS  PubMed  Google Scholar 

  24. Glezer I, Rivest S . Glucocorticoids: protectors of the brain during innate immune responses. Neuroscientist 2004; 10: 538–552.

    Article  CAS  PubMed  Google Scholar 

  25. McEwen BS, Biron CA, Brunson KW, Bulloch K, Chambers WH, Dhabhar FS et al. The role of adrenocorticoids as modulators of immune function in health and disease: neural, endocrine and immune interactions. Brain Res Brain Res Rev 1997; 23: 79–133.

    Article  CAS  PubMed  Google Scholar 

  26. Silverman MN, Sternberg EM . Neuroendocrine-immune interactions in rheumatoid arthritis: mechanisms of glucocorticoid resistance. Neuroimmunomodulation 2008; 15: 19–28.

    Article  CAS  PubMed  Google Scholar 

  27. Webster JI, Sternberg EM . Role of the hypothalamic-pituitary-adrenal axis, glucocorticoids and glucocorticoid receptors in toxic sequelae of exposure to bacterial and viral products. J Endocrinol 2004; 181: 207–221.

    Article  CAS  PubMed  Google Scholar 

  28. Goujon E, Parnet P, Laye S, Combe C, Dantzer R . Adrenalectomy enhances pro-inflammatory cytokines gene expression, in the spleen, pituitary and brain of mice in response to lipopolysaccharide. Brain Res Mol Brain Res 1996; 36: 53–62.

    Article  CAS  PubMed  Google Scholar 

  29. Nadeau S, Rivest S . Glucocorticoids play a fundamental role in protecting the brain during innate immune response. J Neurosci 2003; 23: 5536–5544.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Silverman MN, Macdougall MG, Hu F, Pace TW, Raison CL, Miller AH . Endogenous glucocorticoids protect against TNF-alpha-induced increases in anxiety-like behavior in virally infected mice. Mol Psychiatry 2007; 12: 408–417.

    Article  CAS  PubMed  Google Scholar 

  31. Sternberg EM, Hill JM, Chrousos GP, Kamilaris T, Listwak SJ, Gold PW et al. Inflammatory mediator-induced hypothalamic-pituitary-adrenal axis activation is defective in streptococcal cell wall arthritis-susceptible Lewis rats. Proc Natl Acad Sci USA 1989; 86: 2374–2378.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Goujon E, Parnet P, Aubert A, Goodall G, Dantzer R . Corticosterone regulates behavioral effects of lipopolysaccharide and interleukin-1 beta in mice. Am J Physiol 1995; 269 (1 Part 2): R154–159.

    CAS  PubMed  Google Scholar 

  33. Johnson RW, Propes MJ, Shavit Y . Corticosterone modulates behavioral and metabolic effects of lipopolysaccharide. Am J Physiol 1996; 270 (1 Part 2): R192–198.

    CAS  PubMed  Google Scholar 

  34. Pezeshki G, Pohl T, Schobitz B . Corticosterone controls interleukin-1 beta expression and sickness behavior in the rat. J Neuroendocrinol 1996; 8: 129–135.

    Article  CAS  PubMed  Google Scholar 

  35. Wang D, Lin W, Pan Y, Kuang X, Qi X, Sun H . Chronic blockade of glucocorticoid receptors by RU486 enhances lipopolysaccharide-induced depressive-like behaviour and cytokine production in rats. Brain Behav Immun 2011; 25: 706–714.

    Article  CAS  PubMed  Google Scholar 

  36. Coelho MM, Luheshi G, Hopkins SJ, Pela IR, Rothwell NJ . Multiple mechanisms mediate antipyretic action of glucocorticoids. Am J Physiol 1995; 269 (3 Part 2): R527–535.

    CAS  PubMed  Google Scholar 

  37. Morrow LE, McClellan JL, Conn CA, Kluger MJ . Glucocorticoids alter fever and IL-6 responses to psychological stress and to lipopolysaccharide. Am J Physiol 1993; 264 (5 Part 2): R1010–1016.

    CAS  PubMed  Google Scholar 

  38. Kapcala LP, Chautard T, Eskay RL . The protective role of the hypothalamic-pituitary-adrenal axis against lethality produced by immune, infectious, and inflammatory stress. Ann NY Acad Sci 1995; 771: 419–437.

    Article  CAS  PubMed  Google Scholar 

  39. Ruzek MC, Pearce BD, Miller AH, Biron CA . Endogenous glucocorticoids protect against cytokine-mediated lethality during viral infection. J Immunol 1999; 162: 3527–3533.

    CAS  PubMed  Google Scholar 

  40. Capuron L, Fornwalt FB, Knight BT, Harvey PD, Ninan PT, Miller AH . Does cytokine-induced depression differ from idiopathic major depression in medically healthy individuals? J Affect Disord 2009; 119: 181–185.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Capuron L, Su S, Miller AH, Bremner JD, Goldberg J, Vogt GJ et al. Depressive symptoms and metabolic syndrome: is inflammation the underlying link? Biol Psychiatry 2008; 64: 896–900.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Barnes PJ . Corticosteroid effects on cell signalling. Eur Respir J 2006; 27: 413–426.

    Article  CAS  PubMed  Google Scholar 

  43. Chinenov Y, Rogatsky I . Glucocorticoids and the innate immune system: crosstalk with the toll-like receptor signaling network. Mol Cell Endocrinol 2007; 275: 30–42.

    Article  CAS  PubMed  Google Scholar 

  44. De Bosscher K, Vanden Berghe W, Haegeman G . Cross-talk between nuclear receptors and nuclear factor kappaB. Oncogene 2006; 25: 6868–6886.

    Article  CAS  PubMed  Google Scholar 

  45. Dostert A, Heinzel T . Negative glucocorticoid receptor response elements and their role in glucocorticoid action. Curr Pharm Des 2004; 10: 2807–2816.

    Article  CAS  PubMed  Google Scholar 

  46. Newton R, Holden NS . Separating transrepression and transactivation: a distressing divorce for the glucocorticoid receptor? Mol Pharmacol 2007; 72: 799–809.

    Article  CAS  PubMed  Google Scholar 

  47. Clark AR . Anti-inflammatory functions of glucocorticoid-induced genes. Mol Cell Endocrinol 2007; 275: 79–97.

    Article  CAS  PubMed  Google Scholar 

  48. Schacke H, Docke WD, Asadullah K . Mechanisms involved in the side effects of glucocorticoids. Pharmacol Ther 2002; 96: 23–43.

    Article  CAS  PubMed  Google Scholar 

  49. Reichardt HM, Kaestner KH, Tuckermann J, Kretz O, Wessely O, Bock R et al. DNA binding of the glucocorticoid receptor is not essential for survival. Cell 1998; 93: 531–541.

    Article  CAS  PubMed  Google Scholar 

  50. Kleiman A, Hubner S, Rodriguez Parkitna JM, Neumann A, Hofer S, Weigand MA et al. Glucocorticoid receptor dimerization is required for survival in septic shock via suppression of interleukin-1 in macrophages. FASEB J 2012; 26: 722–729.

    Article  CAS  PubMed  Google Scholar 

  51. Andre C, O’Connor JC, Kelley KW, Lestage J, Dantzer R, Castanon N . Spatio-temporal differences in the profile of murine brain expression of proinflammatory cytokines and indoleamine 2,3-dioxygenase in response to peripheral lipopolysaccharide administration. J Neuroimmunol 2008; 200: 90–99.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Frenois F, Moreau M, O'Connor J, Lawson M, Micon C, Lestage J et al. Lipopolysaccharide induces delayed FosB/DeltaFosB immunostaining within the mouse extended amygdala, hippocampus and hypothalamus, that parallel the expression of depressive-like behavior. Psychoneuroendocrinology 2007; 32: 516–531.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Oitzl MS, Reichardt HM, Joels M, de Kloet ER . Point mutation in the mouse glucocorticoid receptor preventing DNA binding impairs spatial memory. Proc Natl Acad Sci USA 2001; 98: 12790–12795.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Reichardt HM, Tuckermann JP, Gottlicher M, Vujic M, Weih F, Angel P et al. Repression of inflammatory responses in the absence of DNA binding by the glucocorticoid receptor. EMBO J 2001; 20: 7168–7173.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Silverman MN, Miller AH, Biron CA, Pearce BD . Characterization of an interleukin-6- and adrenocorticotropin-dependent, immune-to-adrenal pathway during viral infection. Endocrinology 2004; 145: 3580–3589.

    Article  CAS  PubMed  Google Scholar 

  56. Grose R, Werner S, Kessler D, Tuckermann J, Huggel K, Durka S et al. A role for endogenous glucocorticoids in wound repair. EMBO Rep 2002; 3: 575–582.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Tuckermann JP, Kleiman A, Moriggl R, Spanbroek R, Neumann A, Illing A et al. Macrophages and neutrophils are the targets for immune suppression by glucocorticoids in contact allergy. J Clin Invest 2007; 117: 1381–1390.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Rivest S, Lacroix S, Vallieres L, Nadeau S, Zhang J, Laflamme N . How the blood talks to the brain parenchyma and the paraventricular nucleus of the hypothalamus during systemic inflammatory and infectious stimuli. Proc Soc Exp Biol Med 2000; 223: 22–38.

    Article  CAS  PubMed  Google Scholar 

  59. Marchetti L, Klein M, Schlett K, Pfizenmaier K, Eisel UL . Tumor necrosis factor (TNF)-mediated neuroprotection against glutamate-induced excitotoxicity is enhanced by N-methyl-D-aspartate receptor activation. Essential role of a TNF receptor 2-mediated phosphatidylinositol 3-kinase-dependent NF-kappa B pathway. J Biol Chem 2004; 279: 32869–32881.

    Article  CAS  PubMed  Google Scholar 

  60. Veroni C, Gabriele L, Canini I, Castiello L, Coccia E, Remoli ME et al. Activation of TNF receptor 2 in microglia promotes induction of anti-inflammatory pathways. Mol Cell Neurosci 2010; 45: 234–244.

    Article  CAS  PubMed  Google Scholar 

  61. Lefstin JA, Yamamoto KR . Allosteric effects of DNA on transcriptional regulators. Nature 1998; 392: 885–888.

    Article  CAS  PubMed  Google Scholar 

  62. Miller AH, Spencer RL, Pearce BD, Pisell TL, Azrieli Y, Tanapat P et al. Glucocorticoid receptors are differentially expressed in the cells and tissues of the immune system. Cell Immunol 1998; 186: 45–54.

    Article  CAS  PubMed  Google Scholar 

  63. Ray A, LaForge KS, Sehgal PB . On the mechanism for efficient repression of the interleukin-6 promoter by glucocorticoids: enhancer, TATA box, and RNA start site (Inr motif) occlusion. Mol Cell Biol 1990; 10: 5736–5746.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Zhang G, Zhang L, Duff GW . A negative regulatory region containing a glucocorticosteroid response element (nGRE) in the human interleukin-1beta gene. DNA Cell Biol 1997; 16: 145–152.

    Article  CAS  PubMed  Google Scholar 

  65. Rhoades KL, Golub SH, Economou JS . The regulation of the human tumor necrosis factor alpha promoter region in macrophage, T cell, and B cell lines. J Biol Chem 1992; 267: 22102–22107.

    CAS  PubMed  Google Scholar 

  66. Amano Y, Lee SW, Allison AC . Inhibition by glucocorticoids of the formation of interleukin-1 alpha, interleukin-1 beta, and interleukin-6: mediation by decreased mRNA stability. Mol Pharmacol 1993; 43: 176–182.

    CAS  PubMed  Google Scholar 

  67. Smoak K, Cidlowski JA . Glucocorticoids regulate tristetraprolin synthesis and posttranscriptionally regulate tumor necrosis factor alpha inflammatory signaling. Mol Cell Biol 2006; 26: 9126–9135.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Eskdale J, Kube D, Tesch H, Gallagher G . Mapping of the human IL10 gene and further characterization of the 5′ flanking sequence. Immunogenetics 1997; 46: 120–128.

    Article  CAS  PubMed  Google Scholar 

  69. Franchimont D, Martens H, Hagelstein MT, Louis E, Dewe W, Chrousos GP et al. Tumor necrosis factor alpha decreases, and interleukin-10 increases, the sensitivity of human monocytes to dexamethasone: potential regulation of the glucocorticoid receptor. J Clin Endocrinol Metab 1999; 84: 2834–2839.

    CAS  PubMed  Google Scholar 

  70. Wong ML, Bongiorno PB, Rettori V, McCann SM, Licinio J . Interleukin (IL) 1beta, IL-1 receptor antagonist, IL-10, and IL-13 gene expression in the central nervous system and anterior pituitary during systemic inflammation: pathophysiological implications. Proc Natl Acad Sci USA 1997; 94: 227–232.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Goujon E, Laye S, Parnet P, Dantzer R . Regulation of cytokine gene expression in the central nervous system by glucocorticoids: mechanisms and functional consequences. Psychoneuroendocrinology 1997; 22 (Suppl 1): S75–80.

    Article  CAS  PubMed  Google Scholar 

  72. Quan N, He L, Lai W, Shen T, Herkenham M . Induction of IkappaBalpha mRNA expression in the brain by glucocorticoids: a negative feedback mechanism for immune-to-brain signaling. J Neurosci 2000; 20: 6473–6477.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Laflamme N, Echchannaoui H, Landmann R, Rivest S . Cooperation between toll-like receptor 2 and 4 in the brain of mice challenged with cell wall components derived from gram-negative and gram-positive bacteria. Eur J Immunol 2003; 33: 1127–1138.

    Article  CAS  PubMed  Google Scholar 

  74. Glezer I, Simard AR, Rivest S . Neuroprotective role of the innate immune system by microglia. Neuroscience 2007; 147: 867–883.

    Article  CAS  PubMed  Google Scholar 

  75. Hanisch UK, Johnson TV, Kipnis J . Toll-like receptors: roles in neuroprotection? Trends Neurosci 2008; 31: 176–182.

    Article  CAS  PubMed  Google Scholar 

  76. Frank MG, Miguel ZD, Watkins LR, Maier SF . Prior exposure to glucocorticoids sensitizes the neuroinflammatory and peripheral inflammatory responses to E. coli lipopolysaccharide. Brain Behav Immun 2010; 24: 19–30.

    Article  CAS  PubMed  Google Scholar 

  77. Hermoso MA, Matsuguchi T, Smoak K, Cidlowski JA . Glucocorticoids and tumor necrosis factor alpha cooperatively regulate toll-like receptor 2 gene expression. Mol Cell Biol 2004; 24: 4743–4756.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Homma T, Kato A, Hashimoto N, Batchelor J, Yoshikawa M, Imai S et al. Corticosteroid and cytokines synergistically enhance toll-like receptor 2 expression in respiratory epithelial cells. Am J Respir Cell Mol Biol 2004; 31: 463–469.

    Article  CAS  PubMed  Google Scholar 

  79. Hamelink CR, Currie PJ, Chambers JW, Castonguay TW, Coscina DV . Corticosterone-responsive and -unresponsive metabolic characteristics of adrenalectomized rats. Am J Physiol 1994; 267 (3 Part 2): R799–804.

    CAS  PubMed  Google Scholar 

  80. Linthorst AC, Karanth S, Barden N, Holsboer F, Reul MH . Impaired glucocorticoid receptor function evolves in aberrant physiological responses to bacterial endotoxin. Eur J Neurosci 1999; 11: 178–186.

    Article  CAS  PubMed  Google Scholar 

  81. Richard D, Chapdelaine S, Deshaies Y, Pepin MC, Barden N . Energy balance and lipid metabolism in transgenic mice bearing an antisense GCR gene construct. Am J Physiol 1993; 265 (1 Part 2): R146–150.

    CAS  PubMed  Google Scholar 

  82. Reul JM, Labeur MS, Wiegers GJ, Linthorst AC . Altered neuroimmunoendocrine communication during a condition of chronically increased brain corticotropin-releasing hormone drive. Ann NY Acad Sci 1998; 840: 444–455.

    Article  CAS  PubMed  Google Scholar 

  83. Sternberg EM, Glowa JR, Smith MA, Calogero AE, Listwak SJ, Aksentijevich S et al. Corticotropin releasing hormone related behavioral and neuroendocrine responses to stress in Lewis and Fischer rats. Brain Res 1992; 570: 54–60.

    Article  CAS  PubMed  Google Scholar 

  84. Frijters R, Fleuren W, Toonen EJ, Tuckermann JP, Reichardt HM, van der Maaden H et al. Prednisolone-induced differential gene expression in mouse liver carrying wild type or a dimerization-defective glucocorticoid receptor. BMC Genomics 2010; 11: 359.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  85. Ogimoto K, Harris MK, Wisse BE . MyD88 is a key mediator of anorexia, but not weight loss, induced by lipopolysaccharide and interleukin-1 beta. Endocrinology 2006; 147: 4445–4453.

    Article  CAS  PubMed  Google Scholar 

  86. Roth J . Endogenous antipyretics. Clin Chim Acta 2006; 371: 13–24.

    Article  CAS  PubMed  Google Scholar 

  87. Steiner AA, Romanovsky AA . Leptin: at the crossroads of energy balance and systemic inflammation. Prog Lipid Res 2007; 46: 89–107.

    Article  CAS  PubMed  Google Scholar 

  88. Yirmiya R . Endotoxin produces a depressive-like episode in rats. Brain Res 1996; 711: 163–174.

    Article  CAS  PubMed  Google Scholar 

  89. Yirmiya R, Pollak Y, Barak O, Avitsur R, Ovadia H, Bette M et al. Effects of antidepressant drugs on the behavioral and physiological responses to lipopolysaccharide (LPS) in rodents. Neuropsychopharmacology 2001; 24: 531–544.

    Article  CAS  PubMed  Google Scholar 

  90. Anacker C, Zunszain PA, Carvalho LA, Pariante CM . The glucocorticoid receptor: pivot of depression and of antidepressant treatment? Psychoneuroendocrinology 2011; 36: 415–425.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Manenschijn L, van den Akker EL, Lamberts SW, van Rossum EF . Clinical features associated with glucocorticoid receptor polymorphisms. An overview. Ann NY Acad Sci 2009; 1179: 179–198.

    Article  CAS  PubMed  Google Scholar 

  92. Avitsur R, Powell N, Padgett DA, Sheridan JF . Social interactions, stress, and immunity. Immunol Allergy Clin North Am 2009; 29: 285–293.

    Article  PubMed  Google Scholar 

  93. Black PH . The inflammatory response is an integral part of the stress response: implications for atherosclerosis, insulin resistance, type II diabetes and metabolic syndrome X. Brain Behav Immun 2003; 17: 350–364.

    Article  CAS  PubMed  Google Scholar 

  94. Kiecolt-Glaser JK, Glaser R . Depression and immune function: central pathways to morbidity and mortality. J Psychosom Res 2002; 53: 873–876.

    Article  PubMed  Google Scholar 

  95. Miller GE, Chen E, Sze J, Marin T, Arevalo JM, Doll R et al. A functional genomic fingerprint of chronic stress in humans: blunted glucocorticoid and increased NF-kappaB signaling. Biol Psychiatry 2008; 64: 266–272.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Pace TW, Hu F, Miller AH . Cytokine-effects on glucocorticoid receptor function: relevance to glucocorticoid resistance and the pathophysiology and treatment of major depression. Brain Behav Immun 2007; 21: 9–19.

    Article  CAS  PubMed  Google Scholar 

  97. Rohleder N . Acute and chronic stress induced changes in sensitivity of peripheral inflammatory pathways to the signals of multiple stress systems—2011 Curt Richter Award Winner. Psychoneuroendocrinology 2012; 37: 307–316.

    Article  CAS  PubMed  Google Scholar 

  98. Sorrells SF, Sapolsky RM . An inflammatory review of glucocorticoid actions in the CNS. Brain Behav Immun 2007; 21: 259–272.

    Article  CAS  PubMed  Google Scholar 

  99. Munhoz CD, Sorrells SF, Caso JR, Scavone C, Sapolsky RM . Glucocorticoids exacerbate lipopolysaccharide-induced signaling in the frontal cortex and hippocampus in a dose-dependent manner. J Neurosci 2010; 30: 13690–13698.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Frank MG, Thompson BM, Watkins LR, Maier SF . Glucocorticoids mediate stress-induced priming of microglial pro-inflammatory responses. Brain Behav Immun 2012; 26: 337–345.

    Article  CAS  PubMed  Google Scholar 

  101. Perez-Nievas BG, Madrigal JL, Garcia-Bueno B, Zoppi S, Leza JC . Corticosterone basal levels and vulnerability to LPS-induced neuroinflammation in the rat brain. Brain Res 2010; 1315: 159–168.

    Article  CAS  PubMed  Google Scholar 

  102. Dhabhar FS . Enhancing versus suppressive effects of stress on immune function: implications for immunoprotection and immunopathology. Neuroimmunomodulation 2009; 16: 300–317.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Galon J, Franchimont D, Hiroi N, Frey G, Boettner A, Ehrhart-Bornstein M et al. Gene profiling reveals unknown enhancing and suppressive actions of glucocorticoids on immune cells. FASEB J 2002; 16: 61–71.

    Article  CAS  PubMed  Google Scholar 

  104. Silverman MN, Heim CM, Nater UM, Marques AH, Sternberg EM . Neuroendocrine and immune contributors to fatigue. PMR 2010; 2: 338–346.

    Article  Google Scholar 

  105. De Bosscher K, Van Craenenbroeck K, Meijer OC, Haegeman G . Selective transrepression versus transactivation mechanisms by glucocorticoid receptor modulators in stress and immune systems. Eur J Pharmacol 2008; 583: 290–302.

    Article  CAS  PubMed  Google Scholar 

  106. Kleiman A, Tuckermann JP . Glucocorticoid receptor action in beneficial and side effects of steroid therapy: lessons from conditional knockout mice. Mol Cell Endocrinol 2007; 275: 98–108.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by the NIH (intramural funds from the National Institute of Mental Health (NIMH) to EM Sternberg and from the National Institute on Alcohol Abuse and Alcoholism (NIAAA) to P Pacher). Additional support was received by the Henry M Jackson Foundation (Bethesda, MD, USA—MNS salary) and the Center for Neuroscience and Regenerative Medicine (Uniformed Services University of the Health Sciences, Bethesda, MD, USA). We thank Dr Günther Schütz (German Cancer Research Centre, Heidelberg, Germany) for providing homozygous GRdim mouse breeder pairs to Taconic Farms (Rockville, MD, USA). We also thank Laura Tucker (Uniformed Services University of the Health Sciences, Center for Neuroscience and Regenerative Medicine, Mouse Behavioral Assessment Core, Bethesda, MD, USA) for instruction on the ANY-maze software used to analyze our open field data and Dr Sandor Batkai (Laboratory of Physiologic Studies, NIAAA, NIH, Bethesda, MD, USA) for setting up the metabolic chambers.

Author information

Authors and Affiliations

  1. Section on Neuroendocrine Immunology and Behavior, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA

    M N Silverman, E Belyavskaya, B D Revenis, J H Doran, B E Ballard & E M Sternberg

  2. Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA

    P Mukhopadhyay, J Tam & P Pacher

  3. Department of Psychiatry, Mood and Anxiety Program, University of Maryland School of Medicine, Baltimore, MD, USA

    L H Tonelli

  4. Arizona Center for Integrative Medicine, University of Arizona College of Medicine, Tucson, AZ, USA

    E M Sternberg

Authors
  1. M N Silverman
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. P Mukhopadhyay
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. E Belyavskaya
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. L H Tonelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. B D Revenis
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. J H Doran
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. B E Ballard
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. J Tam
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. P Pacher
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. E M Sternberg
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to E M Sternberg.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Cite this article

Silverman, M., Mukhopadhyay, P., Belyavskaya, E. et al. Glucocorticoid receptor dimerization is required for proper recovery of LPS-induced inflammation, sickness behavior and metabolism in mice. Mol Psychiatry 18, 1006–1017 (2013). https://doi.org/10.1038/mp.2012.131

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/mp.2012.131

Keywords

This article is cited by

Search

Advanced search

Quick links