Effects of tamoxifen on the immune response phenotype in equine peripheral blood mononuclear cells.
Abstract: Tamoxifen (TAM) is widely utilized in the prevention and treatment of human breast cancer and has demonstrated the potential to modulate the immune response. It has been proposed as a therapeutic tool for immune-mediated diseases. TAM has been investigated as a possible treatment for asthma-like conditions in horses, revealing specific impacts on the innate immune system. While the effects of TAM on equine neutrophils are well-documented, its influence on lymphocytes and the modulation of the immune response polarization remains unclear. This study employed peripheral blood mononuclear cells (PBMC) from healthy horses, exposing them to varying concentrations of the TAM and assessing the expression of genes involved in the polarization of the immune response (, , , , , , and ) in PBMC stimulated or not with PMA/ionomycin. Additionally, the effect of TAM over the proportion of regulatory T cells (Treg) was also assessed. TAM did not significantly affect the expression of these genes and Treg at low concentrations. However, at the highest concentration, there was an impact on the expression of , , , and genes. These alterations in genes associated with a Th2 and regulatory response coincided with a noteworthy increase in drug-associated cytotoxicity but only at concentrations far beyond those achieved in pharmacological therapy. These findings suggest that the effects of TAM, as described in preclinical studies on asthmatic horses, may not be attributed to the modification of the adaptive response.
Copyright © 2024 Rodríguez, Quiroga, Cortés, Morán and Henríquez.
Publication Date: 2024-04-10 PubMed ID: 38659456PubMed Central: PMC11041636DOI: 10.3389/fvets.2024.1381162Google Scholar: Lookup
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Summary
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The research article discusses a study exploring the effects of tamoxifen, a drug commonly used for human breast cancer treatment, on the immune response in horse cells. The study particularly scrutinizes how tamoxifen influences the expression of specific genes and regulatory T cells.
Research Context
- This research was conducted in the context of exploring the wide-ranging effects of tamoxifen (TAM), primarily used for preventing and treating human breast cancer, on the immune response of horses.
- The focus was on the influence of TAM on horse lymphocytes and its role in modulating the immune response polarization.
- The study aimed to build upon existing knowledge concerning the effects of TAM on horse neutrophils.
Research Methodology
- Peripheral blood mononuclear cells (PBMC) from healthy horses were used in the study.
- The researchers exposed these cells to different concentrations of TAM and observed the expression of several genes involved in the polarization of the immune response both in the presence and absence of the stimulators PMA/ionomycin.
- The study also investigated the effect of TAM on the proportions of regulatory T cells (Treg).
Research Findings
- The study showed that low concentrations of TAM didn’t significantly affect the expression of the observed genes and Treg.
- However, at higher concentrations, TAM did impact the expression of certain genes associated with Th2 and regulatory responses.
- Noteworthy, the increased expression of these genes correlated with a significant rise in drug-related cytotoxicity. But this cytotoxicity was only evidenced at concentrations considerably higher than those achieved in standard pharmacological treatment.
Research Implications
- The findings suggest that the effects of TAM, as described in preclinical studies on asthmatic horses, may not be attributable to the modification of the adaptive immune response.
- This study helps in expanding the understanding of the intricate interactions between TAM and the equine immune response, which is particularly important for its potential use in treating immune-mediated diseases in horses.
Cite This Article
APA
Rodríguez M, Quiroga J, Cortés B, Morán G, Henríquez C.
(2024).
Effects of tamoxifen on the immune response phenotype in equine peripheral blood mononuclear cells.
Front Vet Sci, 11, 1381162.
https://doi.org/10.3389/fvets.2024.1381162 Publication
Researcher Affiliations
- Instituto de Farmacología y Morfofisiología, Facultad de Ciencias Veterinarias, Universidad Austral de Chile, Valdivia, Chile.
- Instituto de Farmacología y Morfofisiología, Facultad de Ciencias Veterinarias, Universidad Austral de Chile, Valdivia, Chile.
- Instituto de Farmacología y Morfofisiología, Facultad de Ciencias Veterinarias, Universidad Austral de Chile, Valdivia, Chile.
- Instituto de Farmacología y Morfofisiología, Facultad de Ciencias Veterinarias, Universidad Austral de Chile, Valdivia, Chile.
- Instituto de Farmacología y Morfofisiología, Facultad de Ciencias Veterinarias, Universidad Austral de Chile, Valdivia, Chile.
Conflict of Interest Statement
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
References
This article includes 51 references
- Jordan VC. Chemoprevention of breast cancer with selective oestrogen-receptor modulators. Nat Rev Cancer (2007) 7:46–53.
- De M, Jaap A, Dempster J. Tamoxifen therapy in steroid-resistant Riedels disease. Scott Med J (2002) 47:12–3.
- Sereda D, Werth VP. Improvement in dermatomyositis rash associated with the use of antiestrogen medication. Arch Dermatol (2006) 142:70–2.
- Cushman M, Costantino JP, Tracy RP, Song K, Buckley L, Roberts JD. Tamoxifen and cardiac risk factors in healthy women: suggestion of an anti-inflammatory effect. Arterioscler Thromb Vasc Biol (2001) 21:255–61.
- Bonanni B, Johansson H, Gandini S, Guerrieri-Gonzaga A, Sandri MT, Mariette F. Effect of tamoxifen at low doses on ultrasensitive C-reactive protein in healthy women. J Thromb Haemost (2003) 1:2149–52.
- Duffy SM, Lawley WJ, Kaur D, Yang W, Bradding P. Inhibition of human mast cell proliferation and survival by tamoxifen in association with ion channel modulation. J Allergy Clin Immunol (2003) 112:965–72.
- Bharti AC, Aggarwal BB. Nuclear factor-kappa B and cancer: its role in prevention and therapy. Biochem Pharmacol (2002) 64:883–8.
- Takada Y, Bhardwaj A, Potdar P, Aggarwal BB. Nonsteroidal anti-inflammatory agents differ in their ability to suppress NF-κB activation, inhibition of expression of cyclooxygenase-2 and cyclin D1, and abrogation of tumor cell proliferation. Oncogene (2004) 23:9247–58.
- Babina M, Kirn F, Hoser D, Ernst D, Rohde W, Zuberbier T. Tamoxifen counteracts the allergic immune response and improves allergen-induced dermatitis in mice. Clin Exp Allergy (2010) 40:1256–65.
- Sthoeger ZM, Bentwich Z, Zinger H, Mozes E. The beneficial effect of the estrogen antagonist, tamoxifen, on experimental systemic lupus erythematosus. J Rheumatol (1994) 21:2231–8.
- Wu WM, Lin BF, Su YC, Suen JL, Chiang BL. Tamoxifen decreases renal inflammation and alleviates disease severity in autoimmune Nzb/W F1 mice. Scand J Immunol (2000) 52:393–400.
- Wu WM, Suen JL, Lin BF, Chiang BL. Tamoxifen alleviates disease severity and decreases double negative T cells in autoimmune Mrl-lpr/lpr mice. Immunology (2000) 100:110–8.
- Sthoeger ZM, Zinger H, Mozes E. Beneficial effects of the anti-oestrogen tamoxifen on systemic lupus erythematosus of (NZB×NZW)F1 female mice are associated with specific reduction of IgG3 autoantibodies. Ann Rheum Dis (2003) 62:341–6.
- Bebo BF Jr, Dehghani B, Foster S, Kurniawan A, Lopez FJ, Sherman LS. Treatment with selective estrogen receptor modulators regulates myelin specific T-cells and suppresses experimental autoimmune encephalomyelitis. Glia (2009) 57:777–90.
- de Kozak Y, Andrieux K, Villarroya H, Klein C, Thillaye-Goldenberg B, Naud MC. Intraocular injection of tamoxifen-loaded nanoparticles: a new treatment of experimental autoimmune uveoretinitis. Eur J Immunol (2004) 34:3702–12.
- Perez B, Henriquez C, Sarmiento J, Morales N, Folch H, Galesio JS. Tamoxifen as a new therapeutic tool for neutrophilic lung inflammation. Respirology (2016) 21:112–8.
- Mainguy-Seers S, Picotte K, Lavoie JP. Efficacy of tamoxifen for the treatment of severe equine asthma. J Vet Intern Med (2018) 32:1748–53.
- Borlone C, Morales N, Henriquez C, Folch H, Olave C, Sarmiento J. In vitro effects of tamoxifen on equine neutrophils. Res Vet Sci (2017) 110:60–4.
- Olave C, Alvarez P, Uberti B, Morales N, Henriquez C, Folch H. Tamoxifen induces apoptosis and inhibits respiratory burst in equine neutrophils independently of estrogen receptors. J Vet Pharmacol Ther (2019) 42:248–54.
- Morales N, Henriquez C, Sarmiento J, Uberti B, Moran G. Tamoxifen inhibits chemokinesis in equine neutrophils. Ir Vet J (2018) 71:22.
- Sarmiento J, Perez B, Morales N, Henriquez C, Vidal L, Folch H. Apoptotic effects of tamoxifen on leukocytes from horse peripheral blood and bronchoalveolar lavage fluid. Vet Res Commun (2013) 37:333–8.
- Olave C, Morales N, Uberti B, Henriquez C, Sarmiento J, Ortloff A. Tamoxifen induces apoptotic neutrophil efferocytosis in horses. Vet Res Commun (2018) 42:57–63.
- Caffi V, Espinosa G, Gajardo G, Morales N, Duran MC, Uberti B. Pre-conditioning of equine bone marrow-derived mesenchymal stromal cells increases their immunomodulatory capacity. Front Vet Sci (2020) 7:318.
- Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2−ΔΔCT method. Methods (2001) 25:402–8.
- Henriquez C, Perez B, Morales N, Sarmiento J, Carrasco C, Moran G. Participation of T regulatory cells in equine recurrent airway obstruction. Vet Immunol Immunopathol (2014) 158:128–34.
- Rotstein S, Blomgren H, Petrini B, Wasserman J, von Stedingk LV. Influence of adjuvant tamoxifen on blood lymphocytes. Breast Cancer Res Treat (1988) 12:75–9.
- Robinson E, Rubin D, Mekori T, Segal R, Pollack S. In vivo modulation of natural killer cell activity by tamoxifen in patients with bilateral primary breast cancer. Cancer Immunol Immunother (1993) 37:209–12.
- Behjati S, Frank MH. The effects of tamoxifen on immunity. Curr Med Chem (2009) 16:3076–80.
- Ai W, Li H, Song N, Li L, Chen H. Optimal method to stimulate cytokine production and its use in Immunotoxicity assessment. Int J Environ Res Public Health (2013) 10:3834–42.
- Perkins GA, Goodman LB, Wimer C, Freer H, Babasyan S, Wagner B. Maternal T-lymphocytes in equine colostrum express a primarily inflammatory phenotype. Vet Immunol Immunopathol (2014) 161:141–50.
- Siard MH, McMurry KE, Adams AA. Effects of polyphenols including curcuminoids, resveratrol, quercetin, pterostilbene, and hydroxypterostilbene on lymphocyte pro-inflammatory cytokine production of senior horses in vitro. Vet Immunol Immunopathol (2016) 173:50–9.
- Moisa II, Silver CE. Scintigraphic localization of ectopic parathyroid lesions with thallium-201. Head Neck (1991) 13:184–90.
- Maier E, Duschl A, Horejs-Hoeck J. Stat6-dependent and -independent mechanisms in Th2 polarization. Eur J Immunol (2012) 42:2827–33.
- Jacquier V, Estelle J, Schmaltz-Panneau B, Lecardonnel J, Moroldo M, Lemonnier G. Genome-wide immunity studies in the rabbit: transcriptome variations in peripheral blood mononuclear cells after in vitro stimulation by LPS or PMA-ionomycin. BMC Genomics (2015) 16:26.
- Kim JI, Ho IC, Grusby MJ, Glimcher LH. The transcription factor c-Maf controls the production of interleukin-4 but not other Th2 cytokines. Immunity (1999) 10:745–51.
- Nasta F, Ubaldi V, Pace L, Doria G, Pioli C. Cytotoxic T-lymphocyte antigen-4 inhibits GATA-3 but not T-bet mRNA expression during T helper cell differentiation. Immunology (2006) 117:358–67.
- Joffroy CM, Buck MB, Stope MB, Popp SL, Pfizenmaier K, Knabbe C. Antiestrogens induce transforming growth factor beta-mediated immunosuppression in breast cancer. Cancer Res (2010) 70:1314–22.
- Baral E, Nagy E, Berczi I. Modulation of natural killer cell-mediated cytotoxicity by tamoxifen and estradiol. Cancer (1995) 75:591–9.
- Kao CJ, Wurz GT, Lin YC, Vang DP, Phong B, DeGregorio MW. Repurposing ospemifene for potentiating an antigen-specific immune response. Menopause (2017) 24:437–51.
- Polanczyk MJ, Carson BD, Subramanian S, Afentoulis M, Vandenbark AA, Ziegler SF. Cutting edge: estrogen drives expansion of the CD4+ CD25+ regulatory T cell compartment. J Immunol (2004) 173:2227–30.
- Goodman WA, Bedoyan SM, Havran HL, Richardson B, Cameron MJ, Pizarro TT. Impaired estrogen signaling underlies regulatory T cell loss-of-function in the chronically inflamed intestine. Proc Natl Acad Sci USA (2020) 117:17166–76.
- Tai P, Wang J, Jin H, Song X, Yan J, Kang Y. Induction of regulatory T cells by physiological level estrogen. J Cell Physiol (2008) 214:456–64.
- Polanczyk MJ, Hopke C, Vandenbark AA, Offner H. Treg suppressive activity involves estrogen-dependent expression of programmed death-1 (PD-1). Int Immunol (2007) 19:337–43.
- Wang C, Dehghani B, Li Y, Kaler LJ, Proctor T, Vandenbark AA. Membrane estrogen receptor regulates experimental autoimmune encephalomyelitis through up-regulation of programmed death 1. J Immunol (2009) 182:3294–303.
- Roselli M, Cereda V, di Bari MG, Formica V, Spila A, Jochems C. Effects of conventional therapeutic interventions on the number and function of regulatory T cells. Onco Targets Ther (2013) 2:e27025.
- Mantel PY, Kuipers H, Boyman O, Rhyner C, Ouaked N, Ruckert B. GATA3-driven Th2 responses inhibit TGF-beta1-induced FOXP3 expression and the formation of regulatory T cells. PLoS Biol (2007) 5:e329.
- Sabbioni ME, Castiglione M, Hurny C, Siegrist HP, Bacchi M, Bernhard J. Interaction of tamoxifen with concurrent cytotoxic adjuvant treatment affects lymphocytes and lymphocyte subsets counts in breast cancer patients. Support Care Cancer (1999) 7:149–53.
- Torres-Lopez L, Maycotte P, Linan-Rico A, Linan-Rico L, Donis-Maturano L, Delgado-Enciso I. Tamoxifen induces toxicity, causes autophagy, and partially reverses dexamethasone resistance in Jurkat T cells. J Leukoc Biol (2019) 105:983–98.
- Albornoz A, Morales N, Uberti B, Henriquez C, Burgos RA, Alarcon P. Tamoxifen and its metabolites induce mitochondrial membrane depolarization and caspase-3 activation in equine neutrophils. Vet Med Sci (2020) 6:673–8.
- Gajardo G, Lopez-Munoz R, Plaza A, Uberti B, Sarmiento J, Moran G. Tamoxifen in horses: pharmacokinetics and safety study. Ir Vet J (2019) 72:5.
- Jordan VC. New insights into the metabolism of tamoxifen and its role in the treatment and prevention of breast cancer. Steroids (2007) 72:829–42.
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