Abstract
We previously demonstrated the existence of a balance among steroid hormones, i.e. glucocorticoids and androgens, in RACK1 (receptor for activated C kinase 1) expression and innate immunity activation, which may offer the opportunity to use RACK1 expression as marker to evaluate immunotoxicity of hormone-active substances. Because of the existence of close interconnections between the different steroid hormone receptors with overlapping ligand specificities and signaling pathways, in this study, we wanted to investigate a possible effect of estrogenic active compounds, namely 17β-estradiol, diethylstilbestrol, and zearalenone, on RACK-1 expression and innate immune responses using THP-1 cells as experimental model. All compounds increased RACK1 transcriptional activity as evaluated by reporter luciferase activity, mRNA expression as assessed by real time-PCR and protein expression by western blot analysis, which paralleled an increase in LPS-induced IL-8, TNF-α production, and CD86 expression, which we previously demonstrated to be dependent on RACK1/PKCβ activation. As the induction of RACK1 expression can be blocked by the antagonist G15, induced by the agonist G1 and by the non-cell permeable 17β-estradiol conjugated with BSA, a role of GPER (previously named GPR30) activation in estrogen-induced RACK1 expression could be demonstrated. In addition, a role of androgen receptor (AR) in RACK1 transcription was also demonstrated by the ability of flutamide, a nonsteroidal antiandrogen, to completely prevent diethylstilbestrol-induced RACK1 transcriptional activity and protein expression. Altogether, our data suggest that RACK1 may represent an interesting target of steroid-active compounds, and its evaluation may offer the opportunity to screen the immunotoxic potential of hormone-active substances.
Article Highlights
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RACK1 expression is induced by estrogenic active compounds.
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Increased RACK1 levels correlate with increased response to LPS.
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RACK1 evaluation offers the opportunity to screen the immunotoxic potential of steroid hormone-active substances.
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References
Adams DR, Ron D, Kiely PA (2011) RACK1, A multifaceted scaffolding protein: structure and function. Cell Commun Signal 9:22. https://doi.org/10.1186/1478-811X-9-22
Barton M, Filardo EJ, Lolait SJ, Thomas P, Maggiolini M, Prossnitz ER (2018) Twenty years of the G protein-coupled estrogen receptor GPER: historical and personal perspectives. J Steroid Biochem Mol Biol 176:4–15. https://doi.org/10.1016/j.jsbmb.2017.03.021
Bouman A, Heineman MJ, Faas MM (2005) Sex hormones and the immune response in humans. Hum Reprod Update 11(4):411–423. https://doi.org/10.1093/humupd/dmi008
Buoso E, Lanni C, Molteni E, Rousset F, Corsini E, Racchi M (2011) Opposing effects of cortisol and dehydroepiandrosterone on the expression of the receptor for Activated C Kinase 1: implications in immunosenescence. Exp Gerontol 46:877–883. https://doi.org/10.1016/j.exger.2011.07.007
Buoso E, Biundo F, Lanni C, Aiello S, Grossi S, Schettini G, Govoni S, Racchi M (2013) Modulation of Rack-1/PKCβII signalling by soluble AβPPα in SH-SY5Y cells. Curr Alzheimer Res 10:697–705. https://doi.org/10.2174/15672050113109990145
Buoso E, Galasso M, Ronfani M, Papale A, Galbiati V, Eberini I, Marinovich M, Racchi M, Corsini E (2017a) The scaffold protein RACK1 is a target of endocrine disrupting chemicals (EDCs) with important implication in immunity. Toxicol Appl Pharmacol 325:37–47. https://doi.org/10.1016/j.taap.2017.04.011
Buoso E, Galasso M, Ronfani M, Serafini MM, Lanni C, Corsini E, Racchi M (2017b) Role of spliceosome proteins in the regulation of glucocorticoid receptor isoforms by cortisol and dehydroepiandrosterone. Pharmacol Res 120:180–187
Buoso E, Galasso M, Serafini MM, Ronfani M, Lanni C, Corsini E, Racchi M (2017c) Transcriptional regulation of RACK1 and modulation of its expression: role of steroid hormones and significance in health and aging. Cell Signal 35:264–271. https://doi.org/10.1016/j.cellsig.2017.02.010
Cain DW, Cidlowski JA (2017) Immune regulation by glucocorticoids. Nat Rev Immunol 17:233–247. https://doi.org/10.1038/nri.2017.1
Cari L, De Rosa F, Nocentini G, Riccardi C (2019) Context-dependent effect of glucocorticoids on the proliferation, differentiation, and apoptosis of regulatory T cells: a review of the empirical evidence and clinical applications. Int J Mol Sci 20:1142. https://doi.org/10.3390/ijms20051142
Chen CD, Sawyers CL (2002) NF-kappa B activates prostate-specific antigen expression and is upregulated in androgen-independent prostate cancer. Mol Cell Biol 22:2862–2870. https://doi.org/10.1128/mcb.22.8.2862-2870.2002
Chou YC, Chou CC, Chen YK, Tsai S, Hsieh FM, Liu HJ, Hseu TH (1999) Structure and genomic organization of porcine rack1 gene. Biochim Biophys Acta 1489:315–322. https://doi.org/10.1016/s0167-4781(99)00213-4
Coffey K, Robson CN (2012) Regulation of the androgen receptor by post-translational modifications. J Endocrinol 215:221–237. https://doi.org/10.1530/JOE-12-0238
Corsini E, Battaini F, Lucchi L, Marinovich M, Racchi M, Govoni S, Galli CL (1999) A defective protein kinase C anchoring system underlying age-associated impairment in TNF-alpha production in rat macrophages. J Immunol 163:3468–3473
Corsini E, Lucchi L, Meroni M, Racchi M, Solerte B, Fioravanti M, Viviani B, Marinovich M, Govoni S, Galli CL (2002) In vivo dehydroepiandrosterone restores age-associated defects in the protein kinase C signal transduction pathway and related functional responses. J Immunol 168:1753–1758. https://doi.org/10.4049/jimmunol.168.4.1753
Corsini E, Racchi M, Sinforiani E, Lucchi L, Viviani B, Rovati GE, Govoni S, Galli CL, Marinovich M (2005) Age-related decline in RACK1 expression in human leukocytes is correlated to plasma levels of dehydroepiandrosterone. J Leukoc Biol 77:247–256. https://doi.org/10.1189/jlb.0504268
Corsini E, Galbiati V, Esser PR, Pinto A, Racchi M, Marinovich M, Martin SF, Galli CL (2014b) Role of PKC-β in chemical allergen-induced CD86 expression and IL-8 release in THP-1 cells. Arch Toxicol 88:415–424. https://doi.org/10.1007/s00204-013-1144-z
Corsini E, Pinto A, Galbiati V, Viviani B, Galli CL, Marinovich M, Racchi M (2014a) Corticosteroids modulate the expression of the PKC-anchoring protein RACK-1 and cytokine release in THP-1 cells. Pharmacol Res 81:10–16. https://doi.org/10.1016/j.phrs.2014.01.002
Corsini E, Galbiati V, Papale A, Kummer E, Pinto A, Serafini MM, Guaita A, Spezzano R, Caruso D, Marinovich M, Racchi M (2016) Role of androgens in dhea-induced rack1 expression and cytokine modulation in monocytes. Immun Ageing 13:20
Corsini E, Ruffo F, Racchi M (2018) Steroid hormones, endocrine disrupting compounds and immunotoxicology. Curr Opin Toxicol 10:69–73. https://doi.org/10.1016/j.cotox.2018.01.006
Couleau N, Falla J, Beillerot A, Battaglia E, D'Innocenzo M, Plançon S, Laval-Gilly P, Bennasroune A (2015) Effects of endocrine disruptor compounds, alone or in combination, on human macrophage-like THP-1 cell response. PLoS ONE 10:e0131428. https://doi.org/10.1371/journal.pone.0131428
Cutolo M, Carruba G, Villaggio B, Coviello DA, Dayer JM, Campisi I, Miele M, Stefano R, Castagnetta LA (2001) Phorbol diester 12-O-tetradecanoylphorbol 13-acetate (TPA) up-regulates the expression of estrogen receptors in human THP-1 leukemia cells. J Cell Biochem 83(3):390–400. https://doi.org/10.1002/jcb.1237
De Bosscher K, Vanden Berghe W, Haegeman G (2006) Cross-talk between nuclear receptors and nuclear factor kappaB. Oncogene 25:6868–6886. https://doi.org/10.1038/sj.onc.1209935
Del Vecchio I, Zuccotti A, Pisano F, Canneva F, Lenzken SC, Rousset F, Corsini E, Govoni S, Racchi M (2009) Functional mapping of the promoter region of the GNB2L1 human gene coding for RACK1 scaffold protein. Gene 430:17–29. https://doi.org/10.1016/j.gene.2008.10.005
Filardo EJ, Thomas P (2012) Minireview: G protein-coupled estrogen receptor-1, GPER-1: its mechanism of action and role in female reproductive cancer, renal and vascular physiology. Endocrinology 153(7):2953–2962. https://doi.org/10.1210/en.2012-1061
Furman D, Campisi J, Verdin E, Carrera-Bastos P, Targ S, Franceschi C, Ferrucci L, Gilroy DW, Fasano A, Miller GW, Miller AH, Mantovani A, Weyand CM, Barzilai N, Goronzy JJ, Rando TA, Effros RB, Lucia A, Kleinstreuer N, Slavich GM (2019) Chronic inflammation in the etiology of disease across the life span. Nat Med 25:1822–1832. https://doi.org/10.1038/s41591-019-0675-0
Galván-Ramírez ML, Ramírez De Arellano A, Rodríguez-Pérez LR, Lopez-Pulido EI, Muñoz-Valle JF, Pereira-Suárez AL (2019) Hormonal modulation of Toxoplasma gondii infection: Regulation of hormonal receptors and cytokine production in THP-1 cells. Exp Parasitol 204:107721. https://doi.org/10.1016/j.exppara.2019.107721
Guerra-Silveira F, Abad-Franch F (2013) Sex bias in infectious disease epidemiology: patterns and processes. PLoS ONE 4:e62390. https://doi.org/10.1371/journal.pone.0062390
Gupta C (2000) The role of estrogen receptor, androgen receptor and growth factors in diethylstilbestrol-induced programming prostate differentiation. Urol Res 28:223–229. https://doi.org/10.1007/s002400000107
Kemp HA, Read GF, Riad-Fahmy D, Pike AW, Gaskell SJ, Queen K, Harper ME, Griffiths K (1981) Measurement of diethylstilbestrol in plasma from patients with cancer of the prostate. Cancer Res 41:4693–4697
Khurana N, Sikka SC (2018) Targeting crosstalk between Nrf-2, NF-κB and androgen receptor signaling in prostate cancer. Cancers (Basel) 10:352–368. https://doi.org/10.3390/cancers10100352
Kravchenko J, Corsini E, Williams MA, Decker W, Manjili MH, Otsukim T, Singh N, Al-Mulla F, Al-Temaimi R, Amedei A, Colacci AM, Vaccari M, Mondello C, Scovassi AI, Raju J, Hamid RA, Memeo L, Forte S, Roy R, Woodrick J, Salem HK, Ryan EP, Brown DG, Bisson WH, Lowe L, Lyerly HK (2015) Chemical compounds from anthropogenic environment and immune evasion mechanisms: potential interactions. Carcinogenesis 36(Suppl 1):S111–S127. https://doi.org/10.1093/carcin/bgv033
Kuo CH, Yang SN, Kuo PL, Hung CH (2012) Immunomodulatory effects of environmental endocrine disrupting chemicals. Kaohsiung J Med Sci 28:S37–S42. https://doi.org/10.1016/j.kjms.2012.05.008
Laffont S, Seillet C, Guéry JC (2017) Estrogen receptor-dependent regulation of dendritic cell development and function. Front Immunol 8:108. https://doi.org/10.3389/fimmu.2017.00108
Levin ER, Pietras RJ (2008) Estrogen receptors outside the nucleus in breast cancer. Breast Cancer Res Treat 3:351–361. https://doi.org/10.1007/s10549-007-9618-4
Li JJ, Xie D (2015) RACK1, a versatile hub in cancer. Oncogene 34:1890–1898. https://doi.org/10.1038/onc.2014.127
Li L, Wu X, Guan H, Mao B, Wang H, Yuan X, Chu Y, Sun J, Ge RS (2015) Zearalenone inhibits rat and human 11β-hydroxysteroid dehydrogenase type 2. Biomed Res Int 2015:283530. https://doi.org/10.1155/2015/283530
Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 25:402–408. https://doi.org/10.1006/meth.2001.1262
Malinen M, Niskanen EA, Kaikkonen MU, Palvimo JJ (2017) Crosstalk between androgen and pro-inflammatory signaling remodels androgen receptor and NF-κB cistrome to reprogram the prostate cancer cell transcriptome. Nucleic Acids Res. 45:619–630. https://doi.org/10.1093/nar/gkw855
Marttila S, Jylhävä J, Nevalainen T, Nykter M, Jylhä M, Hervonen A, Tserel L, Peterson P, Hurme M (2013) Transcriptional analysis reveals gender-specific changes in the aging of the human immune system. PLoS ONE 8:e66229. https://doi.org/10.1371/journal.pone.0066229
Nadkarni S, McArthur S (2013) Oestrogen and immunomodulation: new mechanisms that impact on peripheral and central immunity. Curr Opin Pharmacol 13:576–581. https://doi.org/10.1016/j.coph.2013.05.007
Nahta R, Al-Mulla F, Al-Temaimi R, Amedei A, Andrade-Vieira R, Bay SN, Brown DG, Calaf GM, Castellino RC, Cohen-Solal KA, Colacci A, Cruickshanks N, Dent P, Di Fiore R, Forte S, Goldberg GS, Hamid RA, Krishnan H, Laird DW, Lasfar A, Marignani PA, Memeo L, Mondello C, Naus CC, Ponce-Cusi R, Raju J, Roy D, Roy R, Ryan EP, Salem HK, Scovassi AI, Singh N, Vaccari M, Vento R, Vondráček J, Wade M, Woodrick J, Bisson WH (2015) Mechanisms of environmental chemicals that enable the cancer hallmark of evasion of growth suppression. Carcinogenesis 36:S2–S18. https://doi.org/10.1093/carcin/bgv028
Nesic K, Ivanovic S, Nesic V (2014) Fusarial toxins: secondary metabolites of Fusarium fungi. Rev Environ Contam Toxicol 228:101–120. https://doi.org/10.1007/978-3-319-01619-1_5
Nowak K, Jabłońska E, Ratajczak-Wrona W (2019) Immunomodulatory effects of synthetic endocrine disrupting chemicals on the development and functions of human immune cells. Environ Int 125:350–364. https://doi.org/10.1016/j.envint.2019.01.078
Pelekanou V, Kampa M, Kiagiadaki F, Deli A, Theodoropoulos P, Agrogiannis G, Patsouris E, Tsapis A, Castanas E, Notas G (2016) Estrogen anti-inflammatory activity on human monocytes is mediated through cross-talk between estrogen receptor ERα36 and GPR30/GPER1. J Leukoc Biol 99:333–347. https://doi.org/10.1189/jlb.3A0914-430RR
Pierdominici M, Maselli A, Colasanti T, Giammarioli AM, Delunardo F, Vacirca D, Sanchez M, Giovannetti A, Malorni W, Ortona E (2010) Estrogen receptor profiles in human peripheral blood lymphocytes. Immunol Lett 132:79–85. https://doi.org/10.1016/j.imlet.2010.06.003
Pihlajamaa P, Sahu B, Jänne OA (2015) Determinants of receptor- and tissue-specific actions in androgen signalling. Endocr Rev 36:357–384. https://doi.org/10.1210/er.2015-1034
Pinto A, Malacrida B, Oieni J, Serafini MM, Davin A, Galbiati V, Corsini E, Racchi M (2015) DHEA modulates the effect of cortisol on RACK1 expression via interference with the splicing of the glucocorticoid receptor. Br J Pharmacol 172:2918–2927. https://doi.org/10.1111/bph.13097
Prossnitz ER, Barton M (2011) The G-protein-coupled estrogen receptor GPER in health and disease. Nat Rev Endocrinol 7:715–726. https://doi.org/10.1038/nrendo.2011.122
Racchi M, Sinforiani E, Govoni S, Marinovich M, Galli CL, Corsini E (2006) RACK-1 expression and cytokine production in leukocytes obtained from AD patients. Aging Clin Exp Res 18:153–157. https://doi.org/10.1007/bf03327432
Racchi M, Buoso E, Ronfani M, Serafini MM, Galasso M, Lanni C, Corsini E (2017) Role of hormones in the regulation of RACK1 expression as a signaling checkpoint in immunosenescence. Int J Mol Sci 18:1453–1465. https://doi.org/10.3390/ijms18071453
Revankar CM, Cimino DF, Sklar LA, Arterburn JB, Prossnitz ER (2005) A transmembrane intracellular estrogen receptor mediates rapid cell signaling. Science 307:1625–1630. https://doi.org/10.1126/science.1106943
Romano SN, Gorelick DA (2018) Crosstalk between nuclear and G protein-coupled estrogen receptors. Gen Comp Endocrinol 261:190–197. https://doi.org/10.1016/j.ygcen.2017.04.013
Ron D, Chen CH, Caldwell J, Jamieson L, Orr E, Mochly-Rosen D (1994) Cloning of an intracellular receptor for protein kinase C: a homolog of the beta subunit of G proteins. Proc Natl Acad Sci USA 91:839–843. https://doi.org/10.1073/pnas.91.3.839
Ron D, Adams DR, Baillie GS, Long A, O'Connor R, Kiely PA (2013) RACK1 to the future–a historical perspective. Cell Commun Signal 11:53. https://doi.org/10.1186/1478-811X-11-53
Rubinow KB (2018) An intracrine view of sex steroids, immunity, and metabolic regulation. Mol Metab. https://doi.org/10.1016/j.molmet.2018.03.001
Sahu B, Pihlajamaa P, Dubois V, Kerkhofs S, Claessens F, Jänne OA (2014) Androgen receptor uses relaxed response element stringency for selective chromatin binding and transcriptional regulation in vivo. Nucleic Acids Res 42:4230–4240. https://doi.org/10.1093/nar/gkt1401
Schauwaers K, De Gendt K, Saunders PT, Atanassova N, Haelens A, Callewaert L, Moehren U, Swinnen JV, Verhoeven G, Verrijdt G, Claessens F (2007) Loss of androgen receptor binding to selective androgen response elements causes a reproductive phenotype in a knockin mouse model. Proc Natl Acad Sci USA 104:4961–4966. https://doi.org/10.1073/pnas.0610814104
Schoenmakers E, Alen P, Verrijdt G, Peeters B, Verhoeven G, Rombauts W, Claessens F (1999) Differential DNA binding by the androgen and glucocorticoid receptors involves the second Zn-finger and a C-terminal extension of the DNA-binding domains. Biochem J 341:515–521
Songsermsakul P, Böhm J, Aurich C, Zentek J, Razzazi-Fazeli E (2013) The levels of zearalenone and its metabolites in plasma, urine and faeces of horses fed with naturally, Fusarium toxin-contaminated oats. J Anim Physiol Anim Nutr (Berl) 97:155–161. https://doi.org/10.1111/j.1439-0396.2011.01253.x
Straub RH (2007) The complex role of estrogens in inflammation. Endocr Rev 28(5):521–574. https://doi.org/10.1210/er.2007-0001
Strehl C, Ehlers L, Gaber T, Buttgereit F (2019) Glucocorticoids-all-rounders tackling the versatile players of the immune system. Front Immunol 10:1744. https://doi.org/10.3389/fimmu.2019.01744
Takada Y, Kato C, Kondo S, Korenaga R, Ando J (1997) Cloning of cDNAs encoding G protein-coupled receptor expressed in human endothelial cells exposed to fluid shear stress. Biochem Biophys Res Commun 240:737–741. https://doi.org/10.1006/bbrc.1997.7734
Teng Y, Radde BN, Litchfield LM, Ivanova MM, Prough RA, Clark BJ, Doll MA, Hein DW, Klinge CM (2015) Dehydroepiandrosterone activation of G-protein-coupled estrogen receptor rapidly stimulates microRNA-21 transcription in human hepatocellular carcinoma cells. J Biol Chem 290:15799–157811. https://doi.org/10.1074/jbc.M115.641167
Thomas P, Dong J (2006) Binding and activation of the seven-transmembrane estrogen receptor GPR30 by environmental estrogens: a potential novel mechanism of endocrine disruption. J Steroid Biochem Mol Biol 102(1–5):175–179. https://doi.org/10.1016/j.jsbmb.2006.09.017
UNEP and WHO (2013) State of the science of endocrine disrupting chemicals 2012. An assessment of the state of the science of endocrine disruptors prepared by a group of experts for the United Nations Environment Programme and World Health Organization. Edited by Åke Bergman, Jerrold J. Heindel, Susan Jobling, Karen A. Kidd and R. Thomas Zoeller. ISBN: 978–92–807–3274–0 (UNEP) and 978 92 4 150503 1 (WHO).
Veurink M, Koster M, Berg LT (2005) The history of DES, lessons to be learned. Pharm World Sci 27:139–143. https://doi.org/10.1007/s11096-005-3663-z
Vine MF, Stein L, Weigle K, Schroeder J, Degnan D, Tse CK, Backer L (2001) Plasma 1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene (DDE) levels and immune response. Am J Epidemiol 153:53–63. https://doi.org/10.1093/aje/153.1.53
Zimmerman MA, Budish RA, Kashyap S, Lindsey SH (2016) GPER-novel membrane oestrogen receptor. Clin Sci (Lond) 130:1005–1016. https://doi.org/10.1093/aje/153.1.53
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Research has been supported by Ministero dell’Istruzione, dell’Università e della Ricerca (PRIN2017, Project number 2017MLC3NF) to Emanuela Corsini. We thank Francesca Pasini for excellent technical assistance.
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Buoso, E., Masi, M., Galbiati, V. et al. Effect of estrogen-active compounds on the expression of RACK1 and immunological implications. Arch Toxicol 94, 2081–2095 (2020). https://doi.org/10.1007/s00204-020-02756-9
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DOI: https://doi.org/10.1007/s00204-020-02756-9