IMMUNE NETWORK

  • 제23권5호
  • /
  • Pages.40.1-40.14
  • /
  • 2023
  • /
  • 1598-2629(pISSN)
  • /
  • 2092-6685(eISSN)
대한면역학회 (The Korean Association of Immunobiologists)
권호 표지

Glucocorticoids Impair the 7α-Hydroxycholesterol-Enhanced Innate Immune Response

  • Yonghae Son (Department of Pharmacology, School of Medicine, Pusan National University) ;
  • Bo-Young Kim (Department of Pharmacology, School of Medicine, Pusan National University) ;
  • Miran Kim (Department of Pharmacology, School of Medicine, Pusan National University) ;
  • Jaesung Kim (Department of Pharmacology, School of Medicine, Pusan National University) ;
  • Ryuk Jun Kwon (Family Medicine Clinic and Research Institute of Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital) ;
  • Koanhoi Kim (Department of Pharmacology, School of Medicine, Pusan National University)
  • 투고 : 2023.09.05
  • 심사 : 2023.10.12
  • 발행 : 2023.10.31
PDF 다운로드
⟨ 이전 논문 다음 논문 ⟩

초록

Glucocorticoids suppress the vascular inflammation that occurs under hypercholesterolemia, as demonstrated in an animal model fed a high-cholesterol diet. However, the molecular mechanisms underlying these beneficial effects remain poorly understood. Because cholesterol is oxidized to form cholesterol oxides (oxysterols) that are capable of inducing inflammation, we investigated whether glucocorticoids affect the immune responses evoked by 7α-hydroxycholesterol (7αOHChol). The treatment of human THP-1 monocytic cells with dexamethasone (Dex) and prednisolone (Pdn) downregulated the expression of pattern recognition receptors (PRRs), such as TLR6 and CD14, and diminished 7αOHChol-enhanced response to FSL-1, a TLR2/6 ligand, and lipopolysaccharide, which interacts with CD14 to initiate immune responses, as determined by the reduced secretion of IL-23 and CCL2, respectively. Glucocorticoids weakened the 7αOHChol-induced production of CCL2 and CCR5 ligands, which was accompanied by decreased migration of monocytic cells and CCR5-expressing Jurkat T cells. Treatment with Dex or Pdn also reduced the phosphorylation of the Akt-1 Src, ERK1/2, and p65 subunits. These results indicate that both Dex and Pdn impair the expression of PRRs and their downstream products, chemokine production, and phosphorylation of signaling molecules. Collectively, glucocorticoids suppress the innate immune response and activation of monocytic cells to an inflammatory phenotype enhanced or induced by 7αOHChol, which may contribute to the anti-inflammatory effects in hypercholesterolemic conditions.

키워드

과제정보

This work was supported by grants from the Basic Science Research Program through the National Research Foundation of Korea (NRF), funded by the Ministry of Education (NRF2019R1I1A3A01055344; K.K.), and a National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIT) (NRF-2022R1F1A107476911; R.J.K.).

참고문헌

  1. Timmermans S, Souffriau J, Libert C. A general introduction to glucocorticoid biology. Front Immunol 2019;10:1545.
  2. Bailey JM, Butler J. Anti-inflammatory drugs in experimental atherosclerosis. I. Relative potencies for inhibiting plaque formation. Atherosclerosis 1973;17:515-522. https://doi.org/10.1016/0021-9150(73)90041-5
  3. Asai K, Funaki C, Hayashi T, Yamada K, Naito M, Kuzuya M, Yoshida F, Yoshimine N, Kuzuya F. Dexamethasone-induced suppression of aortic atherosclerosis in cholesterol-fed rabbits. Possible mechanisms. Arterioscler Thromb 1993;13:892-899. https://doi.org/10.1161/01.ATV.13.6.892
  4. Poon M, Gertz SD, Fallon JT, Wiegman P, Berman JW, Sarembock IJ, Taubman MB. Dexamethasone inhibits macrophage accumulation after balloon arterial injury in cholesterol fed rabbits. Atherosclerosis 2001;155:371-380. https://doi.org/10.1016/S0021-9150(00)00605-5
  5. Joner M, Morimoto K, Kasukawa H, Steigerwald K, Merl S, Nakazawa G, John MC, Finn AV, Acampado E, Kolodgie FD, et al. Site-specific targeting of nanoparticle prednisolone reduces in-stent restenosis in a rabbit model of established atheroma. Arterioscler Thromb Vasc Biol 2008;28:1960-1966. https://doi.org/10.1161/ATVBAHA.108.170662
  6. Rhen T, Cidlowski JA. Antiinflammatory action of glucocorticoids--new mechanisms for old drugs. N Engl J Med 2005;353:1711-1723. https://doi.org/10.1056/NEJMra050541
  7. Hardy RS, Raza K, Cooper MS. Therapeutic glucocorticoids: mechanisms of actions in rheumatic diseases. Nat Rev Rheumatol 2020;16:133-144. https://doi.org/10.1038/s41584-020-0371-y
  8. Brown AJ, Jessup W. Oxysterols and atherosclerosis. Atherosclerosis 1999;142:1-28. https://doi.org/10.1016/S0021-9150(98)00196-8
  9. Carpenter KL, Taylor SE, van der Veen C, Williamson BK, Ballantine JA, Mitchinson MJ. Lipids and oxidised lipids in human atherosclerotic lesions at different stages of development. Biochim Biophys Acta 1995;1256:141-150. https://doi.org/10.1016/0005-2760(94)00247-V
  10. Brown AJ, Leong SL, Dean RT, Jessup W. 7-Hydroperoxycholesterol and its products in oxidized low density lipoprotein and human atherosclerotic plaque. J Lipid Res 1997;38:1730-1745. https://doi.org/10.1016/S0022-2275(20)37148-0
  11. Seo HC, Kim SM, Eo SK, Rhim BY, Kim K. 7α-Hydroxycholesterol elicits TLR6-mediated expression of IL-23 in monocytic cells. Biomol Ther (Seoul) 2015;23:84-89. https://doi.org/10.4062/biomolther.2014.067
  12. Kim SM, Kim BY, Lee SA, Eo SK, Yun Y, Kim CD, Kim K. 27-Hydroxycholesterol and 7alpha-hydroxycholesterol trigger a sequence of events leading to migration of CCR5-expressing Th1 lymphocytes. Toxicol Appl Pharmacol 2014;274:462-470. https://doi.org/10.1016/j.taap.2013.12.007
  13. Kim SM, Kim BY, Son Y, Jung YS, Eo SK, Park YC, Kim K. 7α-Hydroxycholesterol induces inflammation by enhancing production of chemokine (C-C motif ) ligand 2. Biochem Biophys Res Commun 2015;467:879-884. https://doi.org/10.1016/j.bbrc.2015.10.050
  14. Fujiwara N, Kobayashi K. Macrophages in inflammation. Curr Drug Targets Inflamm Allergy 2005;4:281-286. https://doi.org/10.2174/1568010054022024
  15. Kharraz Y, Guerra J, Mann CJ, Serrano AL, Munoz-Canoves P. Macrophage plasticity and the role of inflammation in skeletal muscle repair. Mediators Inflamm 2013;2013:491497.
  16. Zhang C, Yang M, Ericsson AC. Function of macrophages in disease: current understanding on molecular mechanisms. Front Immunol 2021;12:620510.
  17. Park D, Park I, Lee D, Choi YB, Lee H, Yun Y. The adaptor protein Lad associates with the G protein beta subunit and mediates chemokine-dependent T-cell migration. Blood 2007;109:5122-5128. https://doi.org/10.1182/blood-2005-10-061838
  18. Choi J, Kim BY, Son Y, Lee D, Hong YS, Kim MS, Kim K. Reblastatins inhibit phenotypic changes of monocytes/macrophages in a milieu rich in 27-hydroxycholesterol. Immune Netw 2020;20:e17.
  19. Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2-ΔΔCt Method. Methods 2001;25:402-408. https://doi.org/10.1006/meth.2001.1262
  20. Son H, Choi HS, Baek SE, Kim YH, Hur J, Han JH, Moon JH, Lee GS, Park SG, Woo CH, et al. Shear stress induces monocyte/macrophage-mediated inflammation by upregulating cell-surface expression of heat shock proteins. Biomed Pharmacother 2023;161:114566.
  21. Schroder K, Tschopp J. The inflammasomes. Cell 2010;140:821-832. https://doi.org/10.1016/j.cell.2010.01.040
  22. Roh JS, Sohn DH. Damage-associated molecular patterns in inflammatory diseases. Immune Netw 2018;18:e27.
  23. Tang D, Kang R, Coyne CB, Zeh HJ, Lotze MT. PAMPs and DAMPs: signal 0s that spur autophagy and immunity. Immunol Rev 2012;249:158-175. https://doi.org/10.1111/j.1600-065X.2012.01146.x
  24. Takeda K, Kaisho T, Akira S. Toll-like receptors. Annu Rev Immunol 2003;21:335-376. https://doi.org/10.1146/annurev.immunol.21.120601.141126
  25. Takeuchi O, Kawai T, Sanjo H, Copeland NG, Gilbert DJ, Jenkins NA, Takeda K, Akira S. TLR6: a novel member of an expanding toll-like receptor family. Gene 1999;231:59-65. https://doi.org/10.1016/S0378-1119(99)00098-0
  26. Kitchens RL. Role of CD14 in cellular recognition of bacterial lipopolysaccharides. Chem Immunol 2000;74:61-82.  https://doi.org/10.1159/000058750
  27. Chun KH, Seong SY. CD14 but not MD2 transmit signals from DAMP. Int Immunopharmacol 2010;10:98-106. https://doi.org/10.1016/j.intimp.2009.10.002
  28. Ranoa DR, Kelley SL, Tapping RI. Human lipopolysaccharide-binding protein (LBP) and CD14 independently deliver triacylated lipoproteins to Toll-like receptor 1 (TLR1) and TLR2 and enhance formation of the ternary signaling complex. J Biol Chem 2013;288:9729-9741. https://doi.org/10.1074/jbc.M113.453266
  29. Leveque M, Simonin-Le Jeune K, Jouneau S, Moulis S, Desrues B, Belleguic C, Brinchault G, Le Trionnaire S, Gangneux JP, Dimanche-Boitrel MT, et al. Soluble CD14 acts as a DAMP in human macrophages: origin and involvement in inflammatory cytokine/chemokine production. FASEB J 2017;31:1891-1902. https://doi.org/10.1096/fj.201600772R
  30. Takeuchi O, Akira S. Pattern recognition receptors and inflammation. Cell 2010;140:805-820. https://doi.org/10.1016/j.cell.2010.01.022
  31. McKernan DP. Pattern recognition receptors as potential drug targets in inflammatory disorders. Adv Protein Chem Struct Biol 2020;119:65-109. https://doi.org/10.1016/bs.apcsb.2019.09.001
  32. Loetscher P, Uguccioni M, Bordoli L, Baggiolini M, Moser B, Chizzolini C, Dayer JM. CCR5 is characteristic of Th1 lymphocytes. Nature 1998;391:344-345. https://doi.org/10.1038/34814
  33. Roberts CA, Dickinson AK, Taams LS. The interplay between monocytes/macrophages and CD4+  T cell subsets in rheumatoid arthritis. Front Immunol 2015;6:571.
  34. Davignon JL, Hayder M, Baron M, Boyer JF, Constantin A, Apparailly F, Poupot R, Cantagrel A. Targeting monocytes/macrophages in the treatment of rheumatoid arthritis. Rheumatology (Oxford) 2013;52:590-598. https://doi.org/10.1093/rheumatology/kes304
  35. Gordon S, Taylor PR. Monocyte and macrophage heterogeneity. Nat Rev Immunol 2005;5:953-964. https://doi.org/10.1038/nri1733
  36. Ruterbusch M, Pruner KB, Shehata L, Pepper M. In vivo CD4+  T cell differentiation and function: revisiting the Th1/Th2 paradigm. Annu Rev Immunol 2020;38:705-725. https://doi.org/10.1146/annurev-immunol-103019-085803
  37. Baidya SG, Zeng QT. Helper T cells and atherosclerosis: the cytokine web. Postgrad Med J 2005;81:746-752. https://doi.org/10.1136/pgmj.2004.029827
  38. Frostegard J, Ulfgren AK, Nyberg P, Hedin U, Swedenborg J, Andersson U, Hansson GK. Cytokine expression in advanced human atherosclerotic plaques: dominance of pro-inflammatory (Th1) and macrophage-stimulating cytokines. Atherosclerosis 1999;145:33-43. https://doi.org/10.1016/S0021-9150(99)00011-8
  39. Dardalhon V, Korn T, Kuchroo VK, Anderson AC. Role of Th1 and Th17 cells in organ-specific autoimmunity. J Autoimmun 2008;31:252-256. https://doi.org/10.1016/j.jaut.2008.04.017
  40. Shiojima I, Walsh K. Role of Akt signaling in vascular homeostasis and angiogenesis. Circ Res 2002;90:1243-1250. https://doi.org/10.1161/01.RES.0000022200.71892.9F
  41. Lavoie H, Gagnon J, Therrien M. ERK signalling: a master regulator of cell behaviour, life and fate. Nat Rev Mol Cell Biol 2020;21:607-632. https://doi.org/10.1038/s41580-020-0255-7
  42. Cho HR, Son Y, Kim SM, Kim BY, Eo SK, Park YC, Kim K. 7α-Hydroxycholesterol induces monocyte/macrophage cell expression of interleukin-8 via C5a receptor. PLoS One 2017;12:e0173749.
  43. Son Y, Kim BY, Park YC, Eo SK, Cho HR, Kim K. PI3K and ERK signaling pathways are involved in differentiation of monocytic cells induced by 27-hydroxycholesterol. Korean J Physiol Pharmacol 2017;21:301-308. https://doi.org/10.4196/kjpp.2017.21.3.301
  44. Kassel O, Sancono A, Kratzschmar J, Kreft B, Stassen M, Cato AC. Glucocorticoids inhibit MAP kinase via increased expression and decreased degradation of MKP-1. EMBO J 2001;20:7108-7116. https://doi.org/10.1093/emboj/20.24.7108
  45. Wang X, Hu J, Price SR. Inhibition of PI3-kinase signaling by glucocorticoids results in increased branched-chain amino acid degradation in renal epithelial cells. Am J Physiol Cell Physiol 2007;292:C1874-C1879. https://doi.org/10.1152/ajpcell.00617.2006
  46. Cho HR, Kim BY, Kim K, Lee D, Eo SK, Son Y. 27-Hydroxycholesterol induces expression of zonula occludens-1 in monocytic cells via multiple kinases pathways. Sci Rep 2022;12:8213.
  47. Kim BY, Son Y, Kim MS, Kim K. Prednisolone suppresses the immunostimulatory effects of 27-hydroxycholesterol. Exp Ther Med 2020;19:2335-2342. https://doi.org/10.3892/etm.2020.8458
  48. Kim BY, Son Y, Lee J, Choi J, Kim CD, Bae SS, Eo SK, Kim K. Dexamethasone inhibits activation of monocytes/macrophages in a milieu rich in 27-oxygenated cholesterol. PLoS One 2017;12:e0189643.
  49. Ronchetti S, Migliorati G, Bruscoli S, Riccardi C. Defining the role of glucocorticoids in inflammation. Clin Sci (Lond) 2018;132:1529-1543. https://doi.org/10.1042/CS20171505
  50. Hanaoka BY, Peterson CA, Crofford LJ. Glucocorticoid effects on skeletal muscle: benefit and risk in patients with autoimmune inflammatory rheumatoid diseases. Expert Rev Clin Immunol 2012;8:695-697. https://doi.org/10.1586/eci.12.76
  51. Costello RE, Yimer BB, Roads P, Jani M, Dixon WG. Glucocorticoid use is associated with an increased risk of hypertension. Rheumatology (Oxford) 2021;60:132-139. https://doi.org/10.1093/rheumatology/keaa209
  52. Verhoeven F, Prati C, Maguin-Gate K, Wendling D, Demougeot C. Glucocorticoids and endothelial function in inflammatory diseases: focus on rheumatoid arthritis. Arthritis Res Ther 2016;18:258.
  53. Meng X, Chen X, Wu L, Zheng S. The hyperlipidemia caused by overuse of glucocorticoid after liver transplantation and the immune adjustment strategy. J Immunol Res 2017;2017:3149426.