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Original Article

The Effect of Androgens on Proinflammatory Cytokine Secretion from Human Ocular Surface Epithelial Cells

, MD, , PhD, , PhD, , PhD, , PhD, , ORCID Icon & , MDORCID Icon show all
Pages 546-554 | Received 12 Dec 2018, Accepted 24 Oct 2019, Published online: 18 Nov 2019

References

  • Mrugacz M, Ostrowska L, Bryl A, Szulc A, Zelazowska-Rutkowska B, Mrugacz G. Pro-inflammatory cytokines associated with clinical severity of dry eye disease of patients with depression. Adv Med Sci. 2017;62:338–344. doi:10.1016/j.advms.2017.03.003.
  • Benitez-Del-Castillo Sanchez J, Morillo-Rojas MD, Galbis-Estrada C, Pinazo-Duran MD. Determination of inmune response and inflammation mediators in tears: changes in dry eye and glaucoma as compared to healthy controls. Arch Soc Esp Oftalmol. 2017;92:210–217. doi:10.1016/j.oftal.2016.12.009.
  • Nanke Y, Kobashigawa T, Yago T, Kawamoto M, Yamanaka H, Kotake S. Detection of IFN-gamma+IL-17+ cells in salivary glands of patients with Sjogren’s syndrome and Mikulicz’s disease: potential role of Th17*Th1 in the pathogenesis of autoimmune diseases. Nihon Rinsho Meneki Gakkai Kaishi. 2016;39:473–477. doi:10.2177/jsci.39.473.
  • Martin-Montanez V, Enriquez-de-Salamanca A, Lopez-de la Rosa A, et al. Effect of environmental conditions on the concentration of tear inflammatory mediators during contact lens wear. Cornea. 2016;35:1192–1198. doi:10.1097/ICO.0000000000000960.
  • Jung JW, Han SJ, Song MK, et al. Tear cytokines as biomarkers for chronic graft-versus-host disease. Biol Blood Marrow Transplant. 2015;21:2079–2085. doi:10.1016/j.bbmt.2015.08.020.
  • Afonso AA, Sobrin L, Monroy DC, Selzer M, Lokeshwar B, Pflugfelder SC. Tear fluid gelatinase B activity correlates with IL-1alpha concentration and fluorescein clearance in ocular rosacea. Invest Ophthalmol Vis Sci. 1999;40:2506–2512.
  • Solomon A, Dursun D, Liu Z, Xie Y, Macri A, Pflugfelder SC. Pro- and anti-inflammatory forms of interleukin-1 in the tear fluid and conjunctiva of patients with dry-eye disease. Invest Ophthalmol Vis Sci. 2001;42:2283–2292.
  • Barton K, Monroy DC, Nava A, Pflugfelder SC. Inflammatory cytokines in the tears of patients with ocular rosacea. Ophthalmology. 1997;104:1868–1874. doi:10.1016/S0161-6420(97)30014-1.
  • Guenoun JM, Baudouin C, Rat P, Pauly A, Warnet JM, Brignole-Baudouin F. In vitro study of inflammatory potential and toxicity profile of latanoprost, travoprost, and bimatoprost in conjunctiva-derived epithelial cells. Invest Ophthalmol Vis Sci. 2005;46:2444–2450. doi:10.1167/iovs.04-1331.
  • Pisella PJ, Debbasch C, Hamard P, et al. Conjunctival proinflammatory and proapoptotic effects of latanoprost and preserved and unpreserved timolol: an ex vivo and in vitro study. Invest Ophthalmol Vis Sci. 2004;45:1360–1368. doi:10.1167/iovs.03-1067.
  • Cocho L, Fernandez I, Calonge M, et al. Biomarkers in ocular chronic graft versus host disease: tear cytokine- and chemokine-based predictive model. Invest Ophthalmol Vis Sci. 2016;57:746–758. doi:10.1167/iovs.15-18615.
  • Rocha EM, Wickham LA, da Silveira LA, et al. Identification of androgen receptor protein and 5alpha-reductase mRNA in human ocular tissues. Br J Ophthalmol. 2000;84:76–84. doi:10.1136/bjo.84.1.76.
  • Baudouin C. The pathology of dry eye. Surv Ophthalmol. 2001;45(Suppl 2):S211–20. doi:10.1016/S0039-6257(00)00200-9.
  • Jungers P, Nahoul K, Pelissier C, Dougados M, Tron F, Bach JF. Low plasma androgens in women with active or quiescent systemic lupus erythematosus. Arthritis Rheum. 1982;25:454–457. doi:10.1002/art.1780250415.
  • Beeson PB. Age and sex associations of 40 autoimmune diseases. Am J Med. 1994;96:457–462. doi:10.1016/0002-9343(94)90173-2.
  • Cutolo M, Masi AT. Do androgens influence the pathophysiology of rheumatoid arthritis? Facts and hypotheses. J Rheumatol. 1998;25:1041–1047.
  • Valtysdottir ST, Wide L, Hallgren R. Low serum dehydroepiandrosterone sulfate in women with primary Sjogren’s syndrome as an isolated sign of impaired HPA axis function. J Rheumatol. 2001;28:1259–1265.
  • Nightingale J, Chaudhary KS, Abel PD, et al. Ligand activation of the androgen receptor downregulates E-Cadherin-Mediated cell adhesion and promotes apoptosis of prostatic cancer cells. Neoplasia. 2003;5:347–361. doi:10.1016/S1476-5586(03)80028-3.
  • Malkin CJ, Pugh PJ, Jones RD, Kapoor D, Channer KS, Jones TH. The effect of testosterone replacement on endogenous inflammatory cytokines and lipid profiles in hypogonadal men. J Clin Endocrinol Metab. 2004;89:3313–3318. doi:10.1210/jc.2003-031069.
  • Izumi K, Chang C. Targeting inflammatory cytokines-androgen receptor (AR) signaling with ASC-J9(®) to better battle prostate cancer progression. Oncoimmunology. 2013;2(12):e26853.
  • Akashi T, Koizumi K, Nagakawa O, Fuse H, Saiki I. Androgen receptor negatively influences the expression of chemokine receptors (CXCR4, CCR1) and ligand-mediated migration in prostate cancer DU-145. Oncol Rep. 2006;16:831–836.
  • Hoy JJ, Kallifatidis G, Smith DK, Lokeshwar BL Inhibition of androgen receptor promotes CXC-chemokine receptor 7-mediated prostate cancer cell survival. doi: 10.1038/s41598-017-02918-3
  • Hiwatari S. [Protein anabolic steroids in ophthalmology]. Ber Zusammenkunft Dtsch Ophthalmol Ges. 1964;65:424–426.
  • Liu S, Hatton MP, Khandelwal P, Sullivan DA. Culture, immortalization, and characterization of human meibomian gland epithelial cells. Invest Ophthalmol Vis Sci. 2010;51:3993–4005. doi:10.1167/iovs.09-5108.
  • Saruya S. [Studies on allergic conjunctivitis. 5. Effects of castration and sex hormone administration on experimental allergic conjunctivitis]. Nippon Ganka Gakkai Zasshi. 1968;72:833–845.
  • Sullivan DA. Tearful relationships? Sex, hormones, the lacrimal gland, and aqueous-deficient dry eye. Ocul Surf. 2004;2:92–123. doi:10.1016/S1542-0124(12)70147-7.
  • Hedger M, Klug J, Frohlich S, Muller R, Meinhardt A. Regulatory cytokine expression and interstitial fluid formation in the normal and inflamed rat testis are under leydig cell control. J Androl. 2005;26:379–386. doi:10.2164/jandrol.04149.
  • Ongaro L, Castrogiovanni D, Giovambattista A, Gaillard RC, Spinedi E. Enhanced proinflammatory cytokine response to bacterial lipopolysaccharide in the adult male rat after either neonatal or prepubertal ablation of biological testosterone activity. Neuroimmunomodulation. 2011;18:254–260. doi:10.1159/000324125.
  • Osterlund KL, Handa RJ, Gonzales RJ. Dihydrotestosterone alters cyclooxygenase-2 levels in human coronary artery smooth muscle cells. Am J Physiol Endocrinol Metab. 2010;298:E838–45. doi:10.1152/ajpendo.00693.2009.
  • Pergola C, Dodt G, Rossi A, et al. ERK-mediated regulation of leukotriene biosynthesis by androgens: a molecular basis for gender differences in inflammation and asthma. Proc Natl Acad Sci U S A. 2008;105:19881–19886. doi:10.1073/pnas.0809120105.
  • Pergola C, Rogge A, Dodt G, et al. Testosterone suppresses phospholipase D, causing sex differences in leukotriene biosynthesis in human monocytes. Faseb J. 2011;25:3377–3387. doi:10.1096/fj.11-182758.
  • Sahin A, Kam WR, Darabad RR, Topilow K, Sullivan DA. Regulation of leukotriene B4 secretion by human corneal, conjunctival, and meibomian gland epithelial cells. Arch Ophthalmol. 2012;130:1013–1018. doi:10.1001/archophthalmol.2012.1067.
  • Janeway CA Jr., Medzhitov R. Innate immune recognition. Annu Rev Immunol. 2002;20:197–216. doi:10.1146/annurev.immunol.20.083001.084359.
  • Redfern RL, McDermott AM. Toll-like receptors in ocular surface disease. Exp Eye Res. 2010;90:679–687. doi:10.1016/j.exer.2010.03.012.
  • Pearlman E, Johnson A, Adhikary G, et al. Toll-like receptors at the ocular surface. Ocul Surf. 2008;6:108–116. doi:10.1016/S1542-0124(12)70279-3.
  • Chang JH, McCluskey PJ, Wakefield D. Toll-like receptors in ocular immunity and the immunopathogenesis of inflammatory eye disease. British J Ophthalmol. 2006;90:103. doi:10.1136/bjo.2005.072686.
  • Bonini S, Micera A, Iovieno A, Lambiase A, Bonini S. Expression of toll-like receptors in healthy and allergic conjunctiva. Ophthalmology. 2005;112:1528. discussion 1548–9. doi:10.1016/j.ophtha.2005.04.009.
  • He C, Lai P, Weng J, et al. Toll-like receptor 2-mediated NF-kappaB inflammatory responses in dry eye associated with cGVHD. Mol Vis. 2011;17:2605–2611.
  • Lee HS, Hattori T, Park EY, Stevenson W, Chauhan SK, Dana R. Expression of toll-like receptor 4 contributes to corneal inflammation in experimental dry eye disease. Invest Ophthalmol Vis Sci. 2012;53:5632–5640. doi:10.1167/iovs.12-9547.
  • Redfern RL, Patel N, Hanlon S, et al. Toll-like receptor expression and activation in mice with experimental dry eye. Invest Ophthalmol Vis Sci. 2013;54:1554–1563. doi:10.1167/iovs.12-10739.
  • Simmons KT, Xiao Y, Pflugfelder SC, de Paiva CS. Inflammatory response to lipopolysaccharide on the ocular surface in a murine dry eye model. Invest Ophthalmol Vis Sci. 2016;57:2443–2451. doi:10.1167/iovs.15-18396.
  • Gipson IK, Spurr-Michaud S, Argueso P, Tisdale A, Ng TF, Russo CL. Mucin gene expression in immortalized human corneal-limbal and conjunctival epithelial cell lines. Invest Ophthalmol Vis Sci. 2003;44:2496–2506. doi:10.1167/iovs.02-0851.
  • Robertson DM, Li L, Fisher S, et al. Characterization of growth and differentiation in a telomerase-immortalized human corneal epithelial cell line. Invest Ophthalmol Vis Sci. 2005;46:470–478. doi:10.1167/iovs.04-0528.
  • Hui-Zhu C, Kirschenbaum A, Mandeli J, Hollander VP. The effect of dihydrotestosterone and culture conditions on proliferation of the human prostatic cancer cell line LNCaP. Steroids. 1992;57:269–275. doi:10.1016/0039-128X(92)90059-I.
  • Swerdloff RS, Dudley RE, Page ST, Wang C, Salameh WA. Dihydrotestosterone: biochemistry, physiology, and clinical implications of elevated blood levels. Endocr Rev. 2017;38:220–254.
  • Shi H, Guo Y, Liu Y, et al. The in vitro effect of lipopolysaccharide on proliferation, inflammatory factors and antioxidant enzyme activity in bovine mammary epithelial cells. Anim Nutr. 2016;2:99–104. doi:10.1016/j.aninu.2016.03.005.
  • Blais DR, Vascotto SG, Griffith M, Altosaar I. LBP and CD14 secreted in tears by the lacrimal glands modulate the LPS response of corneal epithelial cells. Invest Ophthalmol Vis Sci. 2005;46:4235–4244. doi:10.1167/iovs.05-0543.
  • Reneker LW, Wang L, Irlmeier RT, Huang AJW. Fibroblast Growth Factor Receptor 2 (FGFR2) is required for meibomian gland homeostasis in the adult mouse. Invest Ophthalmol Vis Sci. 2017;58:2638–2646. doi:10.1167/iovs.16-21204.
  • Hou A, Bose T, Chandy KG, Tong L. A chronic autoimmune dry eye rat model with increase in effector memory t cells in eyeball tissue. J Vis Exp. 2017. doi:10.3791/55592.
  • Shatos MA, Hodges RR, Morinaga M, et al. Alteration in cellular turnover and progenitor cell population in lacrimal glands from thrombospondin 1-/- mice, a model of dry eye. Exp Eye Res. 2016;153:27–41. doi:10.1016/j.exer.2016.09.011.
  • Choi W, Noh H, Yeo A, et al. The effect of TNF-alpha blocker HL036337 and its best concentration to inhibit dry eye inflammation. Korean J Ophthalmol. 2016;30:302–308. doi:10.3341/kjo.2016.30.4.302.
  • Lam H, Bleiden L, de Paiva CS, Farley W, Stern ME, Pflugfelder SC. Tear cytokine profiles in dysfunctional tear syndrome. Am J Ophthalmol. 2009;147:198–205 e1. doi:10.1016/j.ajo.2008.08.032.
  • Erdinest N, Shmueli O, Grossman Y, Ovadia H, Solomon A. Anti-inflammatory effects of alpha linolenic acid on human corneal epithelial cells. Invest Ophthalmol Vis Sci. 2012;53:4396–4406. doi:10.1167/iovs.12-9724.
  • Sambursky R. Presence or absence of ocular surface inflammation directs clinical and therapeutic management of dry eye. Clin Ophthalmol. 2016;10:2337–2343. doi:10.2147/OPTH.
  • Barabino S, Horwath-Winter J, Messmer EM, Rolando M, Aragona P, Kinoshita S. The role of systemic and topical fatty acids for dry eye treatment. Prog Retin Eye Res. 2017;61:23–34. doi:10.1016/j.preteyeres.2017.05.003.
  • Li J, Ruzhi D, Hua X, et al. Blueberry component pterostilbene protects corneal epithelial cells from inflammation via anti-oxidative pathway. Sci Rep. 2016;6:19408. doi:10.1038/srep19408.
  • JT E, PC N, RR H, DA D, CN S. Identification and profiling of specialized pro-resolving mediators in human tears by lipid mediator metabolomics. Prostaglandins Leukot Essent Fatty Acids. 2017;117:17–27. doi:10.1016/j.plefa.2017.01.004.
  • Bian F, Pelegrino FS, Henriksson JT, et al. Differential effects of dexamethasone and doxycycline on inflammation and MMP production in murine alkali-burned corneas associated with dry eye. Ocul Surf. 2016;14:242–254. doi:10.1016/j.jtos.2015.11.006.
  • Semba CP, Gadek TR. Development of lifitegrast: a novel T-cell inhibitor for the treatment of dry eye disease. Clin Ophthalmol. 2016;10:1083–1094. doi:10.2147/OPTH.
  • Kocar IH, Yesilova Z, Ozata M, Turan M, Sengul A, Ozdemir I. The effect of testosterone replacement treatment on immunological features of patients with Klinefelter’s syndrome. Clin Exp Immunol. 2000;121:448–452. doi:10.1046/j.1365-2249.2000.01329.x.
  • Ahmed SA, Talal N. Sex hormones and the immune system–part 2. Animal data. Baillieres Clin Rheumatol. 1990;4:13–31. doi:10.1016/S0950-3579(05)80241-9.
  • Friedl R, Brunner M, Moeslinger T, Spieckermann PG. Testosterone inhibits expression of inducible nitric oxide synthase in murine macrophages. Life Sci. 2000;68:417–429. doi:10.1016/S0024-3205(00)00953-X.
  • Kanda N, Tsuchida T, Tamaki K. Testosterone inhibits immunoglobulin production by human peripheral blood mononuclear cells. Clin Exp Immunol. 1996;106:410–415. doi:10.1046/j.1365-2249.1996.d01-842.x.
  • D’Agostino P, Milano S, Barbera C, et al. Sex hormones modulate inflammatory mediators produced by macrophages. Ann N Y Acad Sci. 1999;876:426–429. doi:10.1111/j.1749-6632.1999.tb07667.x.
  • Bebo BF Jr., Schuster JC, Vandenbark AA, Offner H. Androgens alter the cytokine profile and reduce encephalitogenicity of myelin-reactive T cells. J Immunol. 1999;162:35–40.
  • Czerwinski S, Mostafa S, Rowan VS, Azzarolo AM. Time course of cytokine upregulation in the lacrimal gland and presence of autoantibodies in a predisposed mouse model of Sjogren’s syndrome: the influence of sex hormones and genetic background. Exp Eye Res. 2014;128:15–22. doi:10.1016/j.exer.2014.09.001.
  • Hayashi T. Dysfunction of lacrimal and salivary glands in Sjogren’s syndrome: nonimmunologic injury in preinflammatory phase and mouse model. J Biomed Biotechnol. 2011;2011:407031. doi:10.1155/2011/407031.
  • Szodoray P, Alex P, Brun JG, Centola M, Jonsson R. Circulating cytokines in primary Sjogren’s syndrome determined by a multiplex cytokine array system. Scand J Immunol. 2004;59:592–599. doi:10.1111/sji.2004.59.issue-6.
  • Mitsias DI, Tzioufas AG, Veiopoulou C, et al. The Th1/Th2 cytokine balance changes with the progress of the immunopathological lesion of Sjogren’s syndrome. Clin Exp Immunol. 2002;128:562–568. doi:10.1046/j.1365-2249.2002.01869.x.
  • Song X, Zhao P, Wang G, Zhao X. The effects of estrogen and androgen on tear secretion and matrix metalloproteinase-2 expression in lacrimal glands of ovariectomized rats. Invest Ophthalmol Vis Sci. 2014;55:745–751. doi:10.1167/iovs.12-10457.
  • Sullivan DA, Belanger A, Cermak JM, et al. Are women with Sjogren’s syndrome androgen-deficient? J Rheumatol. 2003;30:2413–2419.
  • Sullivan DA, Jensen RV, Suzuki T, Richards SM. Do sex steroids exert sex-specific and/or opposite effects on gene expression in lacrimal and meibomian glands?. Mol Vis. 2009;15:1553–1572.
  • Sullivan DA, Krenzer KL, Sullivan BD, Tolls DB, Toda I, Dana MR. Does androgen insufficiency cause lacrimal gland inflammation and aqueous tear deficiency? Invest Ophthalmol Vis Sci. 1999;40:1261–1265.
  • Quintar AA, Leimgruber C, Pessah OA, Doll A, Maldonado CA. Androgen depletion augments antibacterial prostate host defences in rats. Int J Androl. 2012;35:845–859. doi:10.1111/ija.2012.35.issue-6.
  • Quintar AA, Maldonado CA. Androgen regulation of host defenses and response to inflammatory stimuli in the prostate gland. Cell Biol Int. 2017. doi:10.1002/cbin.10755.
  • Azzarolo AM, Eihausen H, Schechter J. Estrogen prevention of lacrimal gland cell death and lymphocytic infiltration. Exp Eye Res. 2003;77:347–354. doi:10.1016/S0014-4835(03)00120-9.
  • Azzarolo AM, Mircheff AK, Kaswan RL, et al. Androgen support of lacrimal gland function. Endocrine. 1997;6:39–45. doi:10.1007/BF02738800.
  • Azzarolo AM, Wood RL, Mircheff AK, et al. Time course of apoptosis in lacrimal gland after rabbit ovariectomy. Adv Exp Med Biol. 1998;438:523–526.
  • Azzarolo AM, Wood RL, Mircheff AK, et al. Androgen influence on lacrimal gland apoptosis, necrosis, and lymphocytic infiltration. Invest Ophthalmol Vis Sci. 1999;40:592–602.
  • Worda C, Nepp J, Huber JC, Sator MO. Treatment of keratoconjunctivitis sicca with topical androgen. Maturitas. 2001;37:209–212. doi:10.1016/S0378-5122(00)00181-X.
  • Norata GD, Tibolla G, Seccomandi PM, Poletti A, Catapano AL. Dihydrotestosterone decreases tumor necrosis factor-alpha and lipopolysaccharide-induced inflammatory response in human endothelial cells. J Clin Endocrinol Metab. 2006;91:546–554. doi:10.1210/jc.2005-1664.
  • Rettew JA, Huet-Hudson YM, Marriott I. Testosterone reduces macrophage expression in the mouse of toll-like receptor 4, a trigger for inflammation and innate immunity. Biol Reprod. 2008;78:432–437. doi:10.1095/biolreprod.107.063545.
  • Khandelwal P, Liu S, Sullivan DA. Androgen regulation of gene expression in human meibomian gland and conjunctival epithelial cells. Mol Vis. 2012;18:1055–1067.
  • Jabs DA, Prendergast RA, Rorer EM, Hudson AP, Whittum-Hudson JA. Cytokines in autoimmune lacrimal gland disease in MRL/MpJ mice. Invest Ophthalmol Vis Sci. 2001;42:2567–2571.
  • Yavuz S, Akdeniz T, Hancer V, Bicakcigil M, Can M, Yanikkaya-Demirel G. Dual effects of testosterone in Behcet’s disease: implications for a role in disease pathogenesis. Genes Immun. 2016;17:335–341. doi:10.1038/gene.2016.28.
  • Mendes LO, Scarano WR, Rochel-Maia SS, Fioruci-Fontaneli BA, Chuffa LG, Martinez FE. Testosterone therapy differently regulates the anti- and pro-inflammatory cytokines in the plasma and prostate of rats submitted to chronic ethanol consumption (UChB). Am J Reprod Immunol. 2014;72:317–325. doi:10.1111/aji.12268.
  • Chen D, Sahin A, Kam WR, Liu Y, Darabad RR, Sullivan DA. Influence of lipopolysaccharide on proinflammatory gene expression in human corneal, conjunctival and meibomian gland epithelial cells. Ocul Surf. 2018;16:382–389. doi:10.1016/j.jtos.2018.05.003.
  • Harada A, Sekido N, Akahoshi T, Wada T, Mukaida N, Matsushima K. Essential involvement of interleukin-8 (IL-8) in acute inflammation. J Leukoc Biol. 1994;56:559–564. doi:10.1002/jlb.1994.56.issue-5.
  • Ghasemi H. Roles of IL-6 in ocular inflammation: A review. Ocul Immunol Inflamm. 2018;26:37–50. doi:10.1080/09273948.2016.1277247.
  • Stern ME, Pflugfelder SC. Inflammation in dry eye. Ocul Surf. 2004;2:124–130. doi:10.1016/S1542-0124(12)70148-9.
  • Ueta M, Kinoshita S. Innate immunity of the ocular surface. Brain Res Bull. 2010;81:219–228. doi:10.1016/j.brainresbull.2009.10.001.
  • Penn JS, Madan A, Caldwell RB, Bartoli M, Caldwell RW, Hartnett ME. Vascular endothelial growth factor in eye disease. Prog Retin Eye Res. 2008;27:331–371. doi:10.1016/j.preteyeres.2008.05.001.
  • Kommineni VK, Nagineni CN, William A, Detrick B, Hooks JJ. IFN-gamma acts as anti-angiogenic cytokine in the human cornea by regulating the expression of VEGF-A and sVEGF-R1. Biochem Biophys Res Commun. 2008;374:479–484. doi:10.1016/j.bbrc.2008.07.042.
  • Silvestre JS, Mallat Z, Duriez M, et al. Antiangiogenic effect of interleukin-10 in ischemia-induced angiogenesis in mice hindlimb. Circ Res. 2000;87:448–452. doi:10.1161/01.RES.87.6.448.
  • Caffery BE, Joyce E, Heynen ML, Ritter RI, Jones LA, Senchyna M. Quantification of conjunctival TNF-α in aqueous-deficient dry eye. Optom Vis Sci. 2014;91:156–162. doi: 10.1097/OPX.0000000000000133
  • De Paiva CS, Yoon K-C, Pangelinan SB, et al. Cleavage of functional IL-2 receptor alpha chain (CD25) from murine corneal and conjunctival epithelia by MMP-9. J Inflamm (Lond). 2009;6:31. doi:10.1186/1476-9255-6-31.
  • Liu S, Richards SM, Lo K, Hatton M, Fay A, Sullivan DA. Changes in gene expression in human meibomian gland dysfunction. Invest Ophthalmol Vis Sci. 2011;52:2727–2740. doi:10.1167/iovs.10-6482.
  • Qu XD, Lehrer RI. Secretory phospholipase A2 is the principal bactericide for staphylococci and other gram-positive bacteria in human tears. Infect Immun. 1998;66:2791–2797.
  • Hieshima K, Ohtani H, Shibano M, et al. CCL28 has dual roles in mucosal immunity as a chemokine with broad-spectrum antimicrobial activity. J Immunol. 2003;170:1452–1461. doi:10.4049/jimmunol.170.3.1452.
  • Pflugfelder SC, Jones D, Ji Z, Afonso A, Monroy D. Altered cytokine balance in the tear fluid and conjunctiva of patients with Sjögren’s syndrome keratoconjunctivitis sicca. Curr Eye Res. 1999;19:201–211. doi:10.1076/ceyr.19.3.201.5309.
  • Brignole F, Pisella PJ, Goldschild M, De Saint Jean M, Goguel A, Baudouin C. Flow cytometric analysis of inflammatory markers in conjunctival epithelial cells of patients with dry eyes. Invest Ophthalmol Vis Sci. 2000;41:1356–1363.
  • Da Silva JA, Larbre JP, Spector TD, Perry LA, Scott DL, Willoughby DA. Protective effect of androgens against inflammation induced cartilage degradation in male rodents. Ann Rheum Dis. 1993;52:285–291. doi:10.1136/ard.52.4.285.
  • Spence RD, Voskuhl RR. Neuroprotective effects of estrogens and androgens in CNS inflammation and neurodegeneration. Front Neuroendocrinol. 2012;33:105–115. doi:10.1016/j.yfrne.2011.12.001.
  • Gorowska-Wojtowicz E, Hejmej A, Kaminska A, et al. Anti-androgen 2-hydroxyflutamide modulates cadherin, catenin and androgen receptor phosphorylation in androgen-sensitive LNCaP and androgen-independent PC3 prostate cancer cell lines acting via PI3K/Akt and MAPK/ERK1/2 pathways. Toxicol In Vitro. 2017;40:324–335. doi:10.1016/j.tiv.2017.01.019.
  • Kyriakis JM, Avruch J. Mammalian MAPK signal transduction pathways activated by stress and inflammation: a 10-year update. Physiol Rev. 2012;92:689–737. doi:10.1152/physrev.00028.2011.
  • Ueda T, Bruchovsky N, Sadar MD. Activation of the androgen receptor N-terminal domain by interleukin-6 via MAPK and STAT3 signal transduction pathways. J Biol Chem. 2002;277:7076–7085. doi:10.1074/jbc.M108255200.
  • Ansar Ahmed S, Penhale WJ, Talal N. Sex hormones, immune responses, and autoimmune diseases. Mechanisms of sex hormone action. Am J Pathol. 1985;121:531–551.
  • Jansson L, Holmdahl R. Estrogen-mediated immunosuppression in autoimmune diseases. Inflamm Res. 1998;47:290–301. doi:10.1007/s000110050332.
  • Cutolo M, Sulli A, Capellino S, et al. Sex hormones influence on the immune system: basic and clinical aspects in autoimmunity. Lupus. 2004;13:635–638. doi:10.1191/0961203304lu1094oa.
  • Sullivan DA, Wickham LA, Rocha EM, et al. Androgens and dry eye in Sjogren’s syndrome. Ann N Y Acad Sci. 1999;876:312–324. doi:10.1111/j.1749-6632.1999.tb07656.x.
  • Sato EH, Sullivan DA. Comparative influence of steroid hormones and immunosuppressive agents on autoimmune expression in lacrimal glands of a female mouse model of Sjogren’s syndrome. Invest Ophthalmol Vis Sci. 1994;35:2632–2642.
  • Bizzarro A, Valentini G, Di Martino G, DaPonte A, De Bellis A, Iacono G. Influence of testosterone therapy on clinical and immunological features of autoimmune diseases associated with Klinefelter’s syndrome. J Clin Endocrinol Metab. 1987;64:32–36. doi:10.1210/jcem-64-1-32.
  • Araneo BA, Dowell T, Diegel M, Daynes RA. Dihydrotestosterone exerts a depressive influence on the production of interleukin-4 (IL-4), IL-5, and gamma-interferon, but not IL-2 by activated murine T cells. Blood. 1991;78:688–699. doi:10.1182/blood.V78.3.688.688.
  • Popa MA, Mihai MC, Constantin A, et al. Dihydrotestosterone induces pro-angiogenic factors and assists homing of MSC into the cardiac tissue. J Mol Endocrinol. 2018;60:1–15. doi:10.1530/JME-17-0185.
  • Lecce L, Lam YT, Lindsay LA, et al. Aging impairs VEGF-mediated, androgen-dependent regulation of angiogenesis. Mol Endocrinol. 2014;28:1487–1501. doi:10.1210/me.2013-1405.
  • Ding J, WR K, Dieckow J, DA S. The influence of 13-cis retinoic acid on human meibomian gland epithelial cells. Invest Ophthalmol Vis Sci. 2013;54:4341–4350. doi:10.1167/iovs.13-11863.
  • Versura P, Giannaccare G, Campos EC. Sex-steroid imbalance in females and dry eye. Curr Eye Res. 2015;40:162–175. doi:10.3109/02713683.2014.966847.
  • Mayo JC, Hevia D, Quiros-Gonzalez I, et al. IGFBP3 and MAPK/ERK signaling mediates melatonin-induced antitumor activity in prostate cancer. J Pineal Res. 2017;119:62.
  • Sullivan DA, Sullivan BD, Evans JE, et al. Androgen deficiency, Meibomian gland dysfunction, and evaporative dry eye. Ann N Y Acad Sci. 2002;966:211–222. doi:10.1111/nyas.2002.966.issue-1.

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