FREE SHIPPING over $40
OVER 10000 FIVE-STAR REVIEWS
5% OFF ALL SUBSCRIPTIONS
100% HAPPINESS GUARANTEE
Analyze Diet
0
Frontiers in veterinary science2024; 11; 1381162; doi: 10.3389/fvets.2024.1381162

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.
Get Full Text
Publication Date: 2024-04-10 PubMed ID: 38659456PubMed Central: PMC11041636DOI: 10.3389/fvets.2024.1381162Google Scholar: Lookup
The Equine Research Bank provides access to a large database of publicly available scientific literature. Inclusion in the Research Bank does not imply endorsement of study methods or findings by Mad Barn.
LinkedInCopy
  • Journal Article

Summary

This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.

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

Frontiers in veterinary science
ISSN: 2297-1769
NlmUniqueID: 101666658
Country: Switzerland
Language: English
Volume: 11
Pages: 1381162
PII: 1381162

Researcher Affiliations

Rodríguez, Maksimiano
  • Instituto de Farmacología y Morfofisiología, Facultad de Ciencias Veterinarias, Universidad Austral de Chile, Valdivia, Chile.
Quiroga, John
  • Instituto de Farmacología y Morfofisiología, Facultad de Ciencias Veterinarias, Universidad Austral de Chile, Valdivia, Chile.
Cortés, Bayron
  • Instituto de Farmacología y Morfofisiología, Facultad de Ciencias Veterinarias, Universidad Austral de Chile, Valdivia, Chile.
Morán, Gabriel
  • Instituto de Farmacología y Morfofisiología, Facultad de Ciencias Veterinarias, Universidad Austral de Chile, Valdivia, Chile.
Henríquez, Claudio
  • 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
  1. Jordan VC. Chemoprevention of breast cancer with selective oestrogen-receptor modulators. Nat Rev Cancer (2007) 7:46–53.
    doi: 10.1038/nrc2048pubmed: 17186017google scholar: lookup
  2. De M, Jaap A, Dempster J. Tamoxifen therapy in steroid-resistant Riedels disease. Scott Med J (2002) 47:12–3.
    doi: 10.1177/003693300204700106pubmed: 11980291google scholar: lookup
  3. Sereda D, Werth VP. Improvement in dermatomyositis rash associated with the use of antiestrogen medication. Arch Dermatol (2006) 142:70–2.
    doi: 10.1001/archderm.142.1.70pubmed: 16415389google scholar: lookup
  4. 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.
    doi: 10.1161/01.atv.21.2.255pubmed: 11156862google scholar: lookup
  5. 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.
    doi: 10.1046/j.1538-7836.2003.00392.xpubmed: 14521597google scholar: lookup
  6. 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.
    doi: 10.1016/j.jaci.2003.07.004pubmed: 14610489google scholar: lookup
  7. Bharti AC, Aggarwal BB. Nuclear factor-kappa B and cancer: its role in prevention and therapy. Biochem Pharmacol (2002) 64:883–8.
    doi: 10.1016/s0006-2952(02)01154-1pubmed: 12213582google scholar: lookup
  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.
    doi: 10.1038/sj.onc.1208169pubmed: 15489888google scholar: lookup
  9. 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.
    doi: 10.1111/j.1365-2222.2010.03472.xpubmed: 20337649google scholar: lookup
  10. 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.
    pubmed: 7699622
  11. 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.
    doi: 10.1046/j.1365-3083.2000.00789.xpubmed: 11013011google scholar: lookup
  12. 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.
    doi: 10.1046/j.1365-2567.2000.00998.xpmc: PMC2326982pubmed: 10809966google scholar: lookup
  13. 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.
    doi: 10.1136/ard.62.4.341pmc: PMC1754513pubmed: 12634234google scholar: lookup
  14. 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.
    doi: 10.1002/glia.20805pmc: PMC2667209pubmed: 19031437google scholar: lookup
  15. 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.
    doi: 10.1002/eji.200425022pubmed: 15517615google scholar: lookup
  16. 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.
    doi: 10.1111/resp.12664pubmed: 26510482google scholar: lookup
  17. 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.
    doi: 10.1111/jvim.15289pmc: PMC6189378pubmed: 30084157google scholar: lookup
  18. 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.
    doi: 10.1016/j.rvsc.2016.11.003pubmed: 28159238google scholar: lookup
  19. 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.
    doi: 10.1111/jvp.12728pubmed: 30345523google scholar: lookup
  20. Morales N, Henriquez C, Sarmiento J, Uberti B, Moran G. Tamoxifen inhibits chemokinesis in equine neutrophils. Ir Vet J (2018) 71:22.
    doi: 10.1186/s13620-018-0133-1pmc: PMC6199699pubmed: 30386589google scholar: lookup
  21. 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.
    doi: 10.1007/s11259-013-9571-0pubmed: 23846832google scholar: lookup
  22. 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.
    doi: 10.1007/s11259-017-9709-6pubmed: 29297134google scholar: lookup
  23. 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.
    doi: 10.3389/fvets.2020.00318pmc: PMC7325884pubmed: 32656251google scholar: lookup
  24. 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.
    doi: 10.1006/meth.2001.1262pubmed: 11846609google scholar: lookup
  25. 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.
    doi: 10.1016/j.vetimm.2013.12.005pubmed: 24503328google scholar: lookup
  26. 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.
    doi: 10.1007/BF01805743pubmed: 3196888google scholar: lookup
  27. 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.
    doi: 10.1007/BF01525437pmc: PMC11038058pubmed: 8334683google scholar: lookup
  28. Behjati S, Frank MH. The effects of tamoxifen on immunity. Curr Med Chem (2009) 16:3076–80.
    doi: 10.2174/092986709788803042pmc: PMC2902982pubmed: 19689284google scholar: lookup
  29. 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.
    doi: 10.3390/ijerph10093834pmc: PMC3799516pubmed: 23985769google scholar: lookup
  30. 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.
    doi: 10.1016/j.vetimm.2014.07.009pubmed: 25174977google scholar: lookup
  31. 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.
    doi: 10.1016/j.vetimm.2016.04.001pubmed: 27090627google scholar: lookup
  32. Moisa II, Silver CE. Scintigraphic localization of ectopic parathyroid lesions with thallium-201. Head Neck (1991) 13:184–90.
    doi: 10.1002/hed.2880130304pubmed: 2037469google scholar: lookup
  33. Maier E, Duschl A, Horejs-Hoeck J. Stat6-dependent and -independent mechanisms in Th2 polarization. Eur J Immunol (2012) 42:2827–33.
    doi: 10.1002/eji.201242433pmc: PMC3557721pubmed: 23041833google scholar: lookup
  34. 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.
    doi: 10.1186/s12864-015-1218-9pmc: PMC4326531pubmed: 25613284google scholar: lookup
  35. 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.
    doi: 10.1016/s1074-7613(00)80073-4pubmed: 10403649google scholar: lookup
  36. 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.
    doi: 10.1111/j.1365-2567.2005.02309.xpmc: PMC1782225pubmed: 16476055google scholar: lookup
  37. 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.
    doi: 10.1158/0008-5472.CAN-09-3292pubmed: 20145137google scholar: lookup
  38. Baral E, Nagy E, Berczi I. Modulation of natural killer cell-mediated cytotoxicity by tamoxifen and estradiol. Cancer (1995) 75:591–9.
    doi: 10.1002/1097-0142(19950115)75:2<591::aid-cncr2820750224>3.0.co;2-upubmed: 7812928google scholar: lookup
  39. 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.
    doi: 10.1097/GME.0000000000000776pmc: PMC5365365pubmed: 27922937google scholar: lookup
  40. 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.
    doi: 10.4049/jimmunol.173.4.2227pubmed: 15294932google scholar: lookup
  41. 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.
    doi: 10.1073/pnas.2002266117pmc: PMC7382259pubmed: 32632016google scholar: lookup
  42. 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.
    doi: 10.1002/jcp.21221pubmed: 17654501google scholar: lookup
  43. 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.
    doi: 10.1093/intimm/dxl151pubmed: 17267414google scholar: lookup
  44. 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.
    doi: 10.4049/jimmunol.0803205pmc: PMC2729563pubmed: 19234228google scholar: lookup
  45. 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.
    doi: 10.4161/onci.27025pmc: PMC3862634pubmed: 24353914google scholar: lookup
  46. 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.
    doi: 10.1371/journal.pbio.0050329pmc: PMC2222968pubmed: 18162042google scholar: lookup
  47. 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.
    doi: 10.1007/s005200050245pubmed: 10335933google scholar: lookup
  48. 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.
    doi: 10.1002/JLB.2VMA0818-328Rpubmed: 30645008google scholar: lookup
  49. 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.
    doi: 10.1002/vms3.316pmc: PMC7738725pubmed: 32558352google scholar: lookup
  50. 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.
    doi: 10.1186/s13620-019-0143-7pmc: PMC6587269pubmed: 31249663google scholar: lookup
  51. 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.
    doi: 10.1016/j.steroids.2007.07.009pmc: PMC2740485pubmed: 17765940google scholar: lookup

Citations

This article has been cited 0 times.
Subscribe to our newsletter
Join 99,658 horse owners like you who receive our email updates on horse health and nutrition.