Parasites, Hosts and Diseases

The Korea Society for Parasitology and Tropical Medicine (대한기생충학·열대의학회)
권호 표지
DOI QR코드

DOI QR Code

CysLT receptor-mediated NOX2 activation is required for IL-8 production in HMC-1 cells induced by Trichomonas vaginalis-derived secretory products

  • Young Ah Lee (Department of Tropical Medicine and Institute of Tropical Medicine, Yonsei University College of Medicine) ;
  • Myeong Heon Shin (Department of Tropical Medicine and Institute of Tropical Medicine, Yonsei University College of Medicine)
  • Received : 2024.06.28
  • Accepted : 2024.08.11
  • Published : 2024.08.31
Download PDF
⟨ Previous Next ⟩

Abstract

Trichomoniasis is caused by a sexually transmitted flagellate protozoan parasite Trichomonas vaginalis. T. vaginalis-derived secretory products (TvSP) contain lipid mediators such as leukotriene B4 (LTB4) and various cysteinyl leukotrienes (CysLTs) which included LTC4, LTD4, and LTE4. However, the signaling mechanisms by which T. vaginalis-induced CysLTs stimulate interleukin (IL)-8 production in human mast cells remain unclear. In this study, we investigated these mechanisms in human mast cells (HMC-1). Stimulation with TvSP resulted in increased intracellular reactive oxygen species (ROS) generation and NADPH oxidase 2 (NOX2) activation compared to unstimulated cells. Pre-treatment with NOX2 inhibitors such as diphenyleneiodonium chloride (DPI) or apocynin significantly reduced ROS production in TvSP-stimulated HMC-1 cells. Additionally, TvSP stimulation increased NOX2 protein expression and the translocation of p47phox from the cytosol to the membrane. Pretreatment of HMC-1 cells with PI3K or PKC inhibitors reduced TvSP-induced p47phox translocation and ROS generation. Furthermore, NOX2 inhibitors or NOX2 siRNA prevented CREB phosphorylation and IL-8 gene expression or protein secretion induced by TvSP. Pretreatment with a CysLTR antagonist significantly inhibited TvSP-induced ROS production, CREB phosphorylation, and IL-8 production. These results indicate that CysLT-mediated activation of NOX2 plays a crucial role in ROS-dependent IL-8 production in human mast cells stimulated by T. vaginalis-secreted CysLTs. These findings enhance our understanding of the inflammatory response in trichomoniasis and may inform the development of targeted therapies to mitigate this response.

Keywords

Acknowledgement

This study was supported by a National Research Foundation of Korea (NRF) grant funded by the Korean Government (MEST) (NRF-2020R1I1A1A01064838) to YA Lee and by a faculty research grant from the Yonsei University College of Medicine (6-2021-0238) to MH Shin. Authors are grateful to Prof. JS Ryu, Hanyang University Colleage of Medicine for her kind clonation of the T. vaginalis T016 strain.

References

  1. Kobayashi TK, Fujimoto T, Okamoto H, Yuasa M, Sawaragi I. Association of mast cells with vaginal trichomoniasis in endocervical smears. Acta Cytol 1983;27(2):133-137. 
  2. Kim HS, Kawakami Y, Kasakura K, Kawakami T. Recent advances in mast cell activation and regulation. F1000Res 2020;9:F1000 Faculty Rev-196. https://doi.org/10.12688/f1000research.22037.1 
  3. Mukai K, Tsai M, Saito H, Galli SJ. Mast cells as sources of cytokines, chemokines, and growth factors. Immunol Rev 2018;282:121-150. https://doi.org/10.1111/imr.12634 
  4. Matsushima K, Yang D, Oppenheim JJ. Interleukin-8: an evolving chemokine. Cytokine 2022;153:155828. https://doi.org/10.1016/j.cyto.2022.155828 
  5. Mercer F, Johnson PJ. Trichomonas vaginalis: pathogenesis, symbiont interactions, and host cell immune responses. Trends Parasitol 2018;34(8):683-693. https://doi.org/10.1016/j.pt.2018.05.006 
  6. Han IH, Kim JH, Ryu JS. Inflammatory response to Trichomonas vaginalis in the pathogenesis of prostatitis and benign prostatic hyperplasia. Parasites Hosts Dis 2023;61(1):2-14. https://doi.org/10.3347/PHD.22160 
  7. Kummer S, Hayes GR, Gilbert RO, Beach DH, Lucas JJ, et al. Induction of human host cell apoptosis by Trichomonas vaginalis cysteine proteases is modulated by parasite exposure to iron. Microb Pathog 2008;44(3):197-203. https://doi.org/10.1016/j.micpath.2007.09.004 
  8. Szempruch AJ, Dennison L, Kieft R, Harrington JM, Hajduk SL. Sending a message: extracellular vesicles of pathogenic protozoan parasites. Nat Rev Microbiol 2016;14(11):669-675. https://doi.org/10.1038/nrmicro.2016.110 
  9. Shaio MF, Lin PR, Lee CS, Hou SC, Tang P, et al. A novel neutrophil-activating factor released by Trichomonas vaginalis. Infect Immun 1992;60(11):4475-4482. https://doi.org/10.1128/iai.60.11.4475-4482.1992 
  10. Nam YH, Min D, Kim HP, Song KJ, Kim KA, et al. Leukotriene B4 receptor BLT-mediated phosphorylation of NF-κB and CREB is involved in IL-8 production in human mast cells induced by Trichomonas vaginalis-derived secretory products. Microbes Infect 2011;13(14-15):1211-1220. https://doi.org/10.1016/j.micinf.2011.07.006 
  11. Lee YA, Nam YH, Min A, Shin MH. Trichomonas vaginalissecreted cysteinyl leukotrienes promote migration, degranulation and MCP-1 production in mast cells. Parasite Immunol 2020;42(12):e12789. https://doi.org/10.1111/pim.12789 
  12. Nam YH, Min A, Kim SH, Lee YA, Kim KA, et al. Leukotriene B (4) receptors BLT1 and BLT2 are involved in interleukin-8 production in human neutrophils induced by Trichomonas vaginalis-derived secretory products. Inflamm Res 2012;61(2):97-102. https://doi.org/10.1007/s00011-011-0425-3 
  13. Min A, Lee YA, Kim KA, El-Benna J, Shin MH. SNAP23-dependent surface translocation of leukotriene B4 (LTB4) receptor 1 is essential for NOX2-mediated exocytotic degranulation in human mast cells induced by Trichomonas vaginalis-secreted LTB4. Infect Immun 2016;85(1):e00526-16. https://doi.org/10.1128/IAI.00526-16 
  14. Min A, Lee YA, Kim KA, Shin MH. BLT1-mediated O-GlcNAcylation is required for NOX2-dependent migration, exocytotic degranulation and IL-8 release of human mast cell induced by Trichomonas vaginalis-secreted LTB(4). Microbes Infect 2018;20(6):376-384. https://doi.org/10.1016/j.micinf.2018.05.005 
  15. Liu M, Yokomizo T. The role of leukotrienes in allergic diseases. Allergol Int 2015;64(1):17-26. https://doi.org/10.1016/j.alit.2014.09.001 
  16. Kanaoka Y, Austen KF. Roles of cysteinyl leukotrienes and their receptors in immune cell-related functions. Adv Immunol 2019;142:65-84. https://doi.org/10.1016/bs.ai.2019.04.002 
  17. Kim KS, Moon HS, Kim SS, Ryu JS. Involvement of macrophages in proliferation of prostate cancer cells infected with Trichomonas vaginalis. Korean J Parasitol 2021;59(6):557-564. https://doi.org/10.3347/kjp.2021.59.6.557 
  18. Cardamone C, Parente R, Feo GD, Triggiani M. Mast cells as effector cells of innate immunity and regulators of adaptive immunity. Immunol Lett 2016;178:10-14. https://doi.org/10.1016/j.imlet.2016.07.003 
  19. Lejeune M, Moreau F, Chadee K. Prostaglandin E2 produced by Entamoeba histolytica signals via EP4 receptor and alters claudin-4 to increase ion permeability of tight junctions. Am J Pathol 2011;179(2):807-818. https://doi.org/10.1016/j.ajpath.2011.05.001 
  20. Angeli V, Faveeuw C, Roye O, Fontaine J, Teissier E, et al. Role of the parasite-derived prostaglandin D2 in the inhibition of epidermal Langerhans cell migration during schistosomiasis infection. J Exp Med 2001;193(10):1135-1147. https://doi.org/10.1084/jem.193.10.1135 
  21. Nam YH, Min D, Park SJ, Kim KA, Lee YA, et al. NF-кB and CREB are involved in IL-8 production of human neutrophils induced by Trichomonas vaginalis-derived secretory products. Korean J Parasitol 2011;49(3):291-294. https://doi.org/10.3347/kjp.2011.49.3.291 
  22. Thompson C, Cloutier A, Bosse Y, Poisson C, Larivee P, et al. Signaling by the cysteinyl-leukotriene receptor 2. Involvement in chemokine gene transcription. J Biol Chem 2008;283(4):1974-1984. https://doi.org/10.1074/jbc.M608197200 
  23. Thompson C, Cloutier A, Bosse Y, Thivierge M, Gouill CL, et al. CysLT1 receptor engagement induces activator protein-1-and NF-kappaB-dependent IL-8 expression. Am J Respir Cell Mol Biol 2006;35(6):697-704. https://doi.org/10.1165/rcmb.2005-0407OC 
  24. Lin K, Fang S, Cai B, Huang X, Zhang X, et al. ERK/Egr-1 signaling pathway is involved in CysLT2 receptor-mediated IL-8 production in HEK293 cells. Eur J Cell Biol 2014;93(7):278-288. https://doi.org/10.1016/j.ejcb.2014.05.001 
  25. Ichiyama T, Hasegawa S, Umeda M, Terai K, Matsubara T, et al. Pranlukast inhibits NF-kappa B activation in human monocytes/macrophages and T cells. Clin Exp Allergy 2003;33(6):802-827. https://doi.org/10.1046/j.1365-2222.2003.01673.x 
  26. El-Benna J, Dang PM, Gougerot-Pocidalo MA. Priming of the neutrophil NADPH oxidase activation: role of p47phox phosphorylation and NOX2 mobilization to the plasma membrane. Semin Immunopathol 2008;30(3):279-289. https://doi.org/10.1007/s00281-008-0118-3 
  27. Vermot A, Petit-Hartlein I, Smith SME, Fieschi F. NADPH Oxidases (NOX): an overview from discovery, molecular mechanisms to physiology and pathology. Antioxidants (Basel) 2021;10(6):890. https://doi.org/10.3390/antiox10060890 
  28. Lee YA, Shin MH. Involvement of NOX2-derived ROS in human hepatoma HepG2 cell death induced by Entamoeba histolytica. Parasites Hosts Dis 2023;61(4):388-396. https://doi.org/10.3347/PHD.23094