Effects of Dexamethasone on Rat Dendritic Cell Function

Abstract

Glucocorticoids have been reported to affect immunity at varying concentrations. While glucocorticoids have shown profound effects on innate immunity, their effects on rat dendritic cells have not been fully examined. In this study, we evaluated the effects of the synthetic glucocorticoid dexamethasone on cultured rat dendritic cells (DCs) from spleen and derived from bone marrow cells to determine whether responsiveness to dexamethasone varies between DCs from different organ sites. Cells were analyzed for expression of glucocorticoid receptor (GR), the primary receptor through which dexamethasone exerts its effects and was found to be primarily located in the cytoplasm of immature DCs. Bone marrow-derived DCs showed more sensitivity to dexamethasone treatment compared to splenic DCs. Dexamethasone treatment of LPS-matured DCs had profound dose-dependent effects on cytokine production. Dexamethasone treatment also led to a dose-dependent downregulation of expression of costimulatory molecules by mature DCs. Dexamethasone modified immature DC uptake of antigen (FITC-Dextran), with slightly higher numbers of splenic DCs taking up antigen compared to bone marrow-derived DCs. These data suggest that dexamethasone is able to similarly affect both bone marrow-derived and splenic DC function at the immature and mature DC states and could contribute to exacerbation of infection by hindering DC-mediated immune responses.

Steroid hormones - immune cell modulation - antigen presenting/processing

References

• 1 Banchereau J, Steinman RM. Dendritic cells and the control of immunity.  Nature. 1998;  392 245-252
• 2 Kalady MF, Onaitis MW, Emani S, Abdel-Wahab Z, Tyler DS, Pruitt SK. Sequential delivery of maturation stimuli increases human dendritic cell IL-12 production and enhances tumor antigen-specific immunogenicity.  J Surg Res. 2004;  116 24-31
• 3 Rimoldi M, Chieppa M, Larghi P, Vulcano M, Allavena P, Rescigno M. Monocyte-derived dendritic cells activated by bacteria or by bacteria-stimulated epithelial cells are functionally different.  Blood. 2005;  106 2818-2826
• 4 Riboldi E, Musso T, Moroni E, Urbinati C, Bernasconi S, Rusnati M, Adorini L, Presta M, Sozzani S. Cutting edge: proangiogenic properties of alternatively activated dendritic cells.  J Immunol. 2005;  175 2788-2792
• 5 Zeyda M, Saemann MD, Stuhlmeier KM, Mascher DG, Nowotny PN, Zlabinger GJ, Waldhausl W, Stulnig TM. Polyunsaturated fatty acids block dendritic cell activation and function independently of NF-kappaB activation.  J Biol Chem. 2005;  280 14293-14301
• 6 Zhang Z, Li S, Zhang L, Li Y, Lu Y, Wei B, Bu H. The characteristics of tolerogenic plasmacytoid dendritic cells stimulated with interleukin-3.  Transplant Proc. 2005;  37 7-9
• 7 Jiang H, Hou L, Qiao H, Pan S, Zhou B, Liu C, Sun X. Administration of tolerogenic dendritic cells induced by interleukin-10 prolongs rat splenic allograft survival.  Transplant Proc. 2004;  36 3255-3259
• 8 Nikolic T, Geutskens SB, van Rooijen N, Drexhage HA, Leenen PJ. Dendritic cells and macrophages are essential for the retention of lymphocytes in (peri)-insulitis of the nonobese diabetic mouse: a phagocyte depletion study.  Lab Invest. 2005;  85 487-501
• 9 Healey GD, Elvin SJ, Morton M, Williamson ED. Humoral and cell-mediated adaptive immune responses are required for protection against Burkholderia pseudomallei challenge and bacterial clearance postinfection.  Infect Immun. 2005;  73 5945-5951
• 10 Nehete PN, Nehete BP, Manuri P, Hill L, Palmer JL, Sastry KJ. Protection by dendritic cells-based HIV synthetic peptide cocktail vaccine: preclinical studies in the SHIV-rhesus model.  Vaccine. 2005;  23 2154-2159
• 11 Pulendran B. Variegation of the immune response with dendritic cells and pathogen recognition receptors.  J Immunol. 2005;  174 2457-2465
• 12 Kelsall BL, Biron CA, Sharma O, Kaye PM. Dendritic cells at the host-pathogen interface.  Nat Immunol. 2002;  3 699-702
• 13 Elenkov IJ, Wilder RL, Bakalov VK, Link AA, Dimitrov MA, Fisher S, Crane M, Kanik KS, Chrousos GP. IL-12, TNF-alpha, and hormonal changes during late pregnancy and early postpartum: implications for autoimmune disease activity during these times.  J Clin Endocrinol Metab. 2001;  86 4933-4938
• 14 Adcock IM. Glucocorticoids: new mechanisms and future agents.  Curr Allergy Asthma Rep. 2003;  3 249-257
• 15 Webster JI, Tonelli L, Sternberg EM. Neuroendocrine regulation of immunity.  Annu Rev Immunol. 2002;  20 125-163
• 16 Song IH, Buttgereit F. Non-genomic glucocorticoid effects to provide the basis for new drug developments.  Mol Cell Endocrinol. 2006;  246 142-146
• 17 Bruscoli S, Di Virgilio R, Donato V, Velardi E, Baldoni M, Marchetti C, Migliorati G, Riccardi C. Genomic and non-genomic effects of different glucocorticoids on mouse thymocyte apoptosis.  Eur J Pharmacol. 2006;  529 63-70
• 18 Alexandrova M, Mascuchova D, Dobrikova E. Comparison of the effects of dexamethasone 21-acetate and corticosterone on glucocorticoid cytosol receptor depletion and induction of TAT in rat liver.  Endocrinol Exp. 1988;  22 171-179
• 19 De Kloet R, Wallach G, McEwen BS. Differences in corticosterone and dexamethasone binding to rat brain and pituitary.  Endocrinology. 1975;  96 598-609
• 20 Dhabhar FS. Stress-induced augmentation of immune function - the role of stress hormones, leukocyte trafficking, and cytokines.  Brain Behav Immun. 2002;  16 785-798
• 21 Elenkov IJ, Chrousos GP. Stress Hormones, Th1/Th2 patterns, Pro/Anti-inflammatory Cytokines and Susceptibility to Disease.  Trends Endocrinol Metab. 1999;  10 359-368
• 22 Elenkov IJ, Chrousos GP. Stress hormones, proinflammatory and antiinflammatory cytokines, and autoimmunity.  Ann N Y Acad Sci. 2002;  966 290-303
• 23 Woltman AM, Massacrier C, de Fijter JW, Caux C, van Kooten C. Corticosteroids prevent generation of CD34+-derived dermal dendritic cells but do not inhibit Langerhans cell development.  J Immunol. 2002;  168 6181-6188
• 24 Yawalkar N, Karlen S, Egli F, Brand CU, Graber HU, Pichler WJ, Braathen LR. Down-regulation of IL-12 by topical corticosteroids in chronic atopic dermatitis.  J Allergy Clin Immunol. 2000;  106 941-947
• 25 Nakamura K, Saitoh A, Yasaka N, Furue M, Tamaki K. Molecular mechanisms involved in the migration of epidermal dendritic cells in the skin.  J Investig Dermatol Symp Proc. 1999;  4 169-172
• 26 Gormley SM, Armstrong MA, McMurray TJ, McBride WT. The effect of methylprednisolone on cytokine concentration and leukocyte adhesion molecule expression in an isolated cardiopulmonary bypass system.  Cytokine. 2003;  22 149-155
• 27 Elenkov IJ, Chrousos GP, Wilder RL. Neuroendocrine regulation of IL-12 and TNF-alpha/IL-10 balance. Clinical implications.  Ann N Y Acad Sci. 2000;  917 94-105
• 28 Schleimer RP. Glucocorticoids suppress inflammation but spare innate immune responses in airway epithelium.  Proc Am Thorac Soc. 2004;  1 222-230
• 29 Talmor M, Mirza A, Turley S, Mellman I, Hoffman LA, Steinman RM. Generation or large numbers of immature and mature dendritic cells from rat bone marrow cultures.  Eur J Immunol. 1998;  28 811-817
• 30 Arrighi JF, Rebsamen M, Rousset F, Kindler V, Hauser C. A critical role for p38 mitogen-activated protein kinase in the maturation of human blood-derived dendritic cells induced by lipopolysaccharide, TNF-alpha, and contact sensitizers.  J Immunol. 2001;  166 3837-3845
• 31 Sukumar S, Conrad DH, Szakal AK, Tew JG. Differential T cell-mediated regulation of CD23 (Fc epsilonRII) in B cells and follicular dendritic cells.  J Immunol. 2006;  176 4811-4817
• 32 Yamazaki S, Inaba K, Tarbell KV, Steinman RM. Dendritic cells expand antigen-specific Foxp3+CD25+CD4+regulatory T cells including suppressors of alloreactivity.  Immunol Rev. 2006;  212 314-329
• 33 Steinman RM. Dendritic cells and the control of immunity: enhancing the efficiency of antigen presentation.  Mt Sinai J Med. 2001;  68 160-166
• 34 Dhodapkar MV, Krasovsky J, Steinman RM, Bhardwaj N. Mature dendritic cells boost functionally superior CD8(+) T-cell in humans without foreign helper epitopes.  J Clin Invest. 2000;  105 R9-R14
• 35 Boscardin SB, Hafalla JC, Masilamani RF, Kamphorst AO, Zebroski HA, Rai U, Morrot A, Zavala F, Steinman RM, Nussenzweig RS, Nussenzweig MC. Antigen targeting to dendritic cells elicits long-lived T cell help for antibody responses.  J Exp Med. 2006;  203 599-606
• 36 Abraham SM, Lawrence T, Kleiman A, Warden P, Medghalchi M, Tuckermann J, Saklatvala J, Clark AR. Antiinflammatory effects of dexamethasone are partly dependent on induction of dual specificity phosphatase 1.  J Exp Med. 2006;  203 1883-1889
• 37 Nakamura R, Okunuki H, Ishida S, Saito Y, Teshima R, Sawada J. Gene expression profiling of dexamethasone-treated RBL-2H3 cells: induction of anti-inflammatory molecules.  Immunol Lett. 2005;  98 272-279
• 38 Franchimont D, Galon J, Gadina M, Visconti R, Zhou Y, Aringer M, Frucht DM, Chrousos GP, O’Shea JJ. Inhibition of Th1 immune response by glucocorticoids: dexamethasone selectively inhibits IL-12-induced Stat4 phosphorylation in T lymphocytes.  J Immunol. 2000;  164 1768-1774
• 39 Franchimont D, Martens H, Hagelstein MT, Louis E, Dewe W, Chrousos GP, Belaiche J, Geenen V. 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
• 40 Bakker JM, Kavelaars A, Kamphuis PJ, Cobelens PM, van Vugt HH, van Bel F, Heijnen CJ. Neonatal dexamethasone treatment increases susceptibility to experimental autoimmune disease in adult rats.  J Immunol. 2000;  165 5932-5937

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