title: Estrogen alters baseline and inflammatory-induced cytokine levels independent from hypothalamic-pituitary-adrenal axis activity.
abstract: Although estrogen reduces inflammatory-mediated pain responses, the mechanisms behind its effects are unclear. This study investigated if estrogen modulates inflammatory signaling by reducing baseline or inflammation-induced cytokine levels in the injury-site, serum, dorsal root ganglia (DRG) and/or spinal cord. We further tested whether estrogen effects on cytokine levels are in part mediated through hypothalamic-pituitary-adrenal (HPA) axis activation. Lumbar DRG, spinal cord, serum, and hind paw tissue were analyzed for cytokine levels in 17β-estradiol-(20%) or vehicle-(100% cholesterol) treated female rats following ovariectomy/sham adrenalectomy (OVX), adrenalectomy/sham ovariectomy (ADX) or ADX+OVX operation at baseline and post formalin injection. Formalin significantly increased pro-inflammatory interleukin (IL)-6 levels in the paw, as well as pro- and anti-inflammatory cytokine levels in the DRG, spinal cord and serum in comparison to naïve conditions. Estrogen replacement significantly increased anti-inflammatory IL-10 levels in the DRG. Centrally, estradiol significantly decreased pro-inflammatory tumor necrosis factor (TNF)-α and IL-1β levels, as well as IL-10 levels, in the spinal cord in comparison to cholesterol treatment. At both sites, most estradiol modulatory effects occurred irrespective of pain or surgical condition. Estradiol alone had no influence on cytokine release in the paw or serum, indicating that estrogen effects were site-specific. Although cytokine levels were altered between surgical conditions at baseline and following formalin administration, ADX operation did not significantly reverse estradiol's modulation of cytokine levels. These results suggest that estrogen directly regulates cytokines independent of HPA axis activity in vivo, in part by reducing cytokine levels in the spinal cord.
authors: Hunter College and the Graduate Center, The City University of New York, 695 Park Avenue, New York, NY 10065, USA. Electronic address: kshivers15@gmail.com.
authors: Kai-Yvonne
authors: KY
authors: Shivers
authors: Hunter College and the Graduate Center, The City University of New York, 695 Park Avenue, New York, NY 10065, USA.
authors: Nicole
authors: N
authors: Amador
authors: Hunter College and the Graduate Center, The City University of New York, 695 Park Avenue, New York, NY 10065, USA; Rowan University, 201 Mullica Hill Road, Glassboro, NJ 08028, USA.
authors: Lisa
authors: L
authors: Abrams
authors: Hunter College and the Graduate Center, The City University of New York, 695 Park Avenue, New York, NY 10065, USA; Marymount Manhattan College, 221 71st Street, New York, NY 10021, USA.
authors: Deirtra
authors: D
authors: Hunter
authors: Hunter College and the Graduate Center, The City University of New York, 695 Park Avenue, New York, NY 10065, USA.
authors: Shirzad
authors: S
authors: Jenab
authors: Hunter College and the Graduate Center, The City University of New York, 695 Park Avenue, New York, NY 10065, USA.
authors: Vanya
authors: V
authors: Quiñones-Jenab
mesh_terms: D000315:Adrenalectomy; D000818:Animals; D016207:Cytokines / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D004958:Estradiol / Q000008:administration & dosage / Q000494:pharmacology*; D004967:Estrogens / Q000172:deficiency / Q000502:physiology*; D005557:Formaldehyde / Q000008:administration & dosage; D005727:Ganglia, Spinal / Q000276:immunology*; D007030:Hypothalamo-Hypophyseal System / Q000378:metabolism*; D007249:Inflammation; D016753:Interleukin-10 / Q000097:blood / Q000276:immunology; D053583:Interleukin-1beta / Q000097:blood / Q000276:immunology; D015850:Interleukin-6 / Q000097:blood / Q000276:immunology; D010052:Ovariectomy; D010146:Pain; D010913:Pituitary-Adrenal System / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000097:blood / Q000276:immunology
chemical_list: D016207:Cytokines; D004967:Estrogens; D053583:Interleukin-1beta; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D005557:Formaldehyde; D004958:Estradiol
keywords: Adrenalectomy; Cytokines; Estrogen; Inflammation; Ovariectomy
references: Exp Neurol. 2010 Jul;224(1):163-9
references: 20303952
references: Pain. 2010 Dec;151(3):806-15
references: 20926192
references: Pain. 2011 Feb;152(2):419-27
references: 21159431
references: Brain Res. 2011 Mar 25;1382:181-8
references: 21281615
references: Synapse. 2011 Jul;65(7):643-51
references: 21132813
references: J Anesth. 2011 Jun;25(3):392-7
references: 21528403
references: Neurochem Res. 2011 Sep;36(9):1587-93
references: 21127968
references: Neurochem Res. 2011 Oct;36(10):1809-16
references: 21611834
references: Mol Pain. 2012;8:6
references: 22273495
references: Eur J Pain. 2012 Feb;16(2):204-16
references: 22323373
references: Neurol Sci. 2012 Jun;33(3):527-33
references: 21874299
references: Minerva Ginecol. 2012 Jun;64(3):181-94
references: 22635014
references: Rheumatology (Oxford). 2012 Jun;51 Suppl 4:iv14-20
references: 22685271
references: Endocrinology. 2012 Jul;153(7):3337-44
references: 22562172
references: J Trauma Acute Care Surg. 2012 Aug;73(2):408-12
references: 22846947
references: Joint Bone Spine. 2013 Jul;80(4):368-73
references: 23352515
references: J Neurotrauma. 2013 Aug 1;30(15):1311-24
references: 23731227
references: Mediators Inflamm. 2013;2013:480739
references: 23997430
references: J Neurophysiol. 2013 Oct;110(7):1663-71
references: 23864372
references: J Neurotrauma. 1999 Oct;16(10):851-63
references: 10547095
references: Endocrinology. 2000 Apr;141(4):1455-63
references: 10746650
references: Spine (Phila Pa 1976). 2000 May 15;25(10):1206-17
references: 10806496
references: Endocrinology. 2000 Jul;141(7):2526-31
references: 10875254
references: Endocrinology. 2000 Oct;141(10):3646-56
references: 11014219
references: Annu Rev Immunol. 2002;20:125-63
references: 11861600
references: Int J Neurosci. 2002 Jun;112(6):665-703
references: 12325311
references: J Neurosci. 2003 Apr 1;23(7):2517-21
references: 12684435
references: Pain. 2003 Aug;104(3):655-64
references: 12927638
references: Obstet Gynecol Clin North Am. 2011 Sep;38(3):477-88
references: 21961715
references: Front Biosci (Elite Ed). 2012;4:976-97
references: 22201929
references: Endocrinology. 2004 Nov;145(11):5021-32
references: 15256495
references: Brain Res. 2005 Jun 14;1047(1):119-22
references: 15893295
references: Pain. 2005 Aug;116(3):257-63
references: 15964142
references: Endocrinology. 2005 Aug;146(8):3301-8
references: 15860553
references: Cytokine. 2005 Aug 21;31(4):251-7
references: 16043358
references: J Immunol. 2005 Nov 15;175(10):6509-16
references: 16272305
references: J Leukoc Biol. 2005 Dec;78(6):1215-22
references: 16204636
references: Behav Brain Res. 2006 Feb 28;167(2):355-64
references: 16256210
references: Horm Behav. 2006 Apr;49(4):441-9
references: 16257405
references: Brain Res Rev. 2006 Aug;51(2):240-64
references: 16388853
references: Pain. 2006 Dec 15;126(1-3):294-308
references: 16949747
references: J Pain. 2007 Apr;8(4):334-42
references: 17140856
references: Brain Behav Immun. 2007 Jul;21(5):686-98
references: 17174526
references: Brain Behav Immun. 2007 Jul;21(5):660-7
references: 17204394
references: Brain Res. 2008 Apr 8;1203:177-88
references: 18316064
references: J Neuroimmunol. 2008 Mar;195(1-2):47-59
references: 18328572
references: Immunol Rev. 2008 Dec;226:19-28
references: 19161413
references: Exp Brain Res. 2009 Jun;196(1):67-78
references: 19290516
references: Brain Behav Immun. 2009 Oct;23(7):958-68
references: 19464360
references: Arthritis Res Ther. 2009;11(5):241
references: 19804619
references: PLoS One. 2010;5(2):e9421
references: 20195535
references: Ethn Dis. 2010 Winter;20(1 Suppl 1):S1-50-4
references: 20521385
references: J Neurosci Methods. 2004 Jun 15;136(1):87-98
references: 15126049
references: Neurosci Lett. 2004 May 6;361(1-3):184-7
references: 15135924
references: Nature. 1988 Aug 25;334(6184):698-700
references: 3137474
references: Am J Pathol. 1991 Feb;138(2):395-402
references: 1992764
references: J Clin Oncol. 1991 Apr;9(4):694-704
references: 2066765
references: Proc Natl Acad Sci U S A. 1992 Jun 1;89(11):4888-92
references: 1594589
references: Br J Pharmacol. 1992 Nov;107(3):660-4
references: 1472964
references: Life Sci. 1993;52(7):677-85
references: 8429760
references: Ann N Y Acad Sci. 1995 Dec 29;771:419-37
references: 8597419
references: Brain Res Brain Res Rev. 1995 Nov;21(3):246-84
references: 8806016
references: J Clin Endocrinol Metab. 1997 Jul;82(7):2182-91
references: 9215292
references: Neuroscience. 1997 Nov;81(1):255-62
references: 9300418
references: J Clin Invest. 1997 Dec 1;100(11):2641-7
references: 9389725
references: J Neuroendocrinol. 2004 Dec;16(12):989-98
references: 15667454
references: Pharmacol Biochem Behav. 2005 Apr;80(4):603-10
references: 15820530
references: Neurosci Lett. 2005 May 13;379(3):209-13
references: 15843065
references: Clin Immunol. 2005 May;115(2):162-72
references: 15885639