The Korean Journal of Physiology and Pharmacology

The Korean Society of Pharmacology (대한약리학회)
권호 표지
DOI QR코드

DOI QR Code

LPS Increases 5-LO Expression on Monocytes via an Activation of Akt-Sp1/NF-${\kappa}B$ Pathways

  • Lee, Seung Jin (Department of Pharmacology and BK21 Medical Science Education Center, School of Medicine, Pusan National University) ;
  • Seo, Kyo Won (Department of Pharmacology and BK21 Medical Science Education Center, School of Medicine, Pusan National University) ;
  • Kim, Chi Dae (Department of Pharmacology and BK21 Medical Science Education Center, School of Medicine, Pusan National University)
  • Received : 2015.01.05
  • Accepted : 2015.03.21
  • Published : 2015.05.01
Download PDF
⟨ Previous Next ⟩

Abstract

5-Lipoxygenase (5-LO) plays a pivotal role in the progression of atherosclerosis. Therefore, this study investigated the molecular mechanisms involved in 5-LO expression on monocytes induced by LPS. Stimulation of THP-1 monocytes with LPS ($0{\sim}3{\mu}g/ml$) increased 5-LO promoter activity and 5-LO protein expression in a concentration-dependent manner. LPS-induced 5-LO expression was blocked by pharmacological inhibition of the Akt pathway, but not by inhibitors of MAPK pathways including the ERK, JNK, and p38 MAPK pathways. In line with these results, LPS increased the phosphorylation of Akt, suggesting a role for the Akt pathway in LPS-induced 5-LO expression. In a promoter activity assay conducted to identify transcription factors, both Sp1 and NF-${\kappa}B$ were found to play central roles in 5-LO expression in LPS-treated monocytes. The LPS-enhanced activities of Sp1 and NF-${\kappa}B$ were attenuated by an Akt inhibitor. Moreover, the LPS-enhanced phosphorylation of Akt was significantly attenuated in cells pretreated with an anti-TLR4 antibody. Taken together, 5-LO expression in LPS-stimulated monocytes is regulated at the transcriptional level via TLR4/Akt-mediated activations of Sp1 and NF-${\kappa}B$ pathways in monocytes.

Keywords

References

  1. Badimon L, Storey RF, Vilahur G. Update on lipids, inflammation and atherothrombosis. Thromb Haemost. 2011;105 Suppl 1:S34-42. https://doi.org/10.1160/THS10-11-0717
  2. Hansson GK. Inflammatory mechanisms in atherosclerosis. J Thromb Haemost. 2009;7 Suppl 1:328-331. https://doi.org/10.1111/j.1538-7836.2009.03416.x
  3. Gupta H, Dai L, Datta G, Garber DW, Grenett H, Li Y, Mishra V, Palgunachari MN, Handattu S, Gianturco SH, Bradley WA, Anantharamaiah GM, White CR. Inhibition of lipopolysaccharide-induced inflammatory responses by an apolipoprotein AI mimetic peptide. Circ Res. 2005;97:236-243. https://doi.org/10.1161/01.RES.0000176530.66400.48
  4. Kuhn AM, Tzieply N, Schmidt MV, von Knethen A, Namgaladze D, Yamamoto M, Brune B. Antioxidant signaling via Nrf2 counteracts lipopolysaccharide-mediated inflammatory responses in foam cell macrophages. Free Radic Biol Med. 2011;50:1382-1391. https://doi.org/10.1016/j.freeradbiomed.2011.02.036
  5. Sikorski K, Chmielewski S, Przybyl L, Heemann U, Wesoly J, Baumann M, Bluyssen HA. STAT1-mediated signal integration between IFN${\gamma}$ and LPS leads to increased EC and SMC activation and monocyte adhesion. Am J Physiol Cell Physiol. 2011;300: C1337-1344. https://doi.org/10.1152/ajpcell.00276.2010
  6. Poeckel D, Funk CD. The 5-lipoxygenase/leukotriene pathway in preclinical models of cardiovascular disease. Cardiovasc Res. 2010;86:243-253. https://doi.org/10.1093/cvr/cvq016
  7. Vila L. Cyclooxygenase and 5-lipoxygenase pathways in the vessel wall: role in atherosclerosis. Med Res Rev. 2004;24:399-424. https://doi.org/10.1002/med.10065
  8. Mehrabian M, Allayee H. 5-lipoxygenase and atherosclerosis. Curr Opin Lipidol. 2003;14:447-457. https://doi.org/10.1097/00041433-200310000-00005
  9. Yonekawa K, Neidhart M, Altwegg LA, Wyss CA, Corti R, Vogl T, Grigorian M, Gay S, Lucher TF, Maier W. Myeloid related proteins activate Toll-like receptor 4 in human acute coronary syndromes. Atherosclerosis. 2011;218:486-492. https://doi.org/10.1016/j.atherosclerosis.2011.06.020
  10. Kawamoto T, Ii M, Kitazaki T, Iizawa Y, Kimura H. TAK-242 selectively suppresses Toll-like receptor 4-signaling mediated by the intracellular domain. Eur J Pharmacol. 2008;584:40-48. https://doi.org/10.1016/j.ejphar.2008.01.026
  11. Serio KJ, Reddy KV, Bigby TD. Lipopolysaccharide induces 5-lipoxygenase-activating protein gene expression in THP-1 cells via a NF-kappaB and C/EBP-mediated mechanism. Am J Physiol Cell Physiol. 2005;288:C1125-1133. https://doi.org/10.1152/ajpcell.00296.2004
  12. Zhao L, Moos MP, Graner R, Pedrono F, Fan J, Kaiser B, John N, Schmidt S, Spanbroek R, Lotzer K, Huang L, Cui J, Rader DJ, Evans JF, Habenicht AJ, Funk CD. The 5-lipoxygenase pathway promotes pathogenesis of hyperlipidemia-dependent aortic aneurysm. Nat Med. 2004;10:966-973. https://doi.org/10.1038/nm1099
  13. De Caterina R, Zampolli A. From asthma to atherosclerosis--5-lipoxygenase, leukotrienes, and inflammation. N Engl J Med. 2004;350:4-7. https://doi.org/10.1056/NEJMp038190
  14. Jawien J. The putative role of leukotrienes in experimental atherogenesis. Pol Arch Med Wewn. 2009;119:90-93.
  15. Radmark O, Werz O, Steinhilber D, Samuelsson B. 5-Lipoxygenase: regulation of expression and enzyme activity. Trends Biochem Sci. 2007;32:332-341. https://doi.org/10.1016/j.tibs.2007.06.002
  16. Lotzer K, Funk CD, Habenicht AJ. The 5-lipoxygenase pathway in arterial wall biology and atherosclerosis. Biochim Biophys Acta. 2005;1736:30-37.
  17. Yang HJ, Youn H, Seong KM, Yun YJ, Kim W, Kim YH, Lee JY, Kim CS, Jin YW, Youn B. Psoralidin, a dual inhibitor of COX-2 and 5-LOX, regulates ionizing radiation (IR)-induced pulmonary inflammation. Biochem Pharmacol. 2011;82:524-534. https://doi.org/10.1016/j.bcp.2011.05.027
  18. Sanchez-Galan E, Gomez-Hernandez A, Vidal C, Martin- Ventura JL, Blanco-Colio LM, Munoz-Garcia B, Ortega L, Egido J, Tunon J. Leukotriene B4 enhances the activity of nuclear factorkappaB pathway through BLT1 and BLT2 receptors in atherosclerosis. Cardiovasc Res. 2009;81:216-225. https://doi.org/10.1093/cvr/cvn277
  19. Hansson GK, Hermansson A. The immune system in atherosclerosis. Nat Immunol. 2011;12:204-212.
  20. Drueke TB, Massy ZA. Atherosclerosis in CKD: differences from the general population. Nat Rev Nephrol. 2010;6:723-735. https://doi.org/10.1038/nrneph.2010.143
  21. Gitlin JM, Loftin CD. Cyclooxygenase-2 inhibition increases lipopolysaccharide-induced atherosclerosis in mice. Cardiovasc Res. 2009;81:400-407.
  22. Szeto CC, Kwan BC, Chow KM, Lai KB, Chung KY, Leung CB, Li PK. Endotoxemia is related to systemic inflammation and atherosclerosis in peritoneal dialysis patients. Clin J Am Soc Nephrol. 2008;3:431-436. https://doi.org/10.2215/CJN.03600807
  23. Lalla E, Lamster IB, Hofmann MA, Bucciarelli L, Jerud AP, Tucker S, Lu Y, Papapanou PN, Schmidt AM. Oral infection with a periodontal pathogen accelerates early atherosclerosis in apolipoprotein E-null mice. Arterioscler Thromb Vasc Biol. 2003;23:1405-1411. https://doi.org/10.1161/01.ATV.0000082462.26258.FE
  24. Serio KJ, Reddy KV, Bigby TD. Lipopolysaccharide induces 5-lipoxygenase-activating protein gene expression in THP-1 cells via a NF-kappaB and C/EBP-mediated mechanism. Am J Physiol Cell Physiol. 2005;288:C1125-1133. https://doi.org/10.1152/ajpcell.00296.2004
  25. Lee SJ, Kim CE, Seo KW, Kim CD. HNE-induced 5-LO expression is regulated by NF-{kappa}B/ERK and Sp1/p38 MAPK pathways via EGF receptor in murine macrophages. Cardiovasc Res. 2010;88:352-359. https://doi.org/10.1093/cvr/cvq194
  26. Serezani CH, Lewis C, Jancar S, Peters-Golden M. Leukotriene B4 amplifies NF-κB activation in mouse macrophages by reducing SOCS1 inhibition of MyD88 expression. J Clin Invest. 2011;121:671-682. https://doi.org/10.1172/JCI43302

Cited by

  1. Inactivation of PI3-K/Akt and reduction of SP1 and p65 expression increase the effect of solamargine on suppressing EP4 expression in human lung cancer cells vol.34, pp.1, 2015, https://doi.org/10.1186/s13046-015-0272-0
  2. Neutrophils recruited by leukotriene B4 induce features of plaque destabilization during endotoxaemia vol.114, pp.12, 2015, https://doi.org/10.1093/cvr/cvy130
  3. Regulation of Eicosanoid Pathways by MicroRNAs vol.10, pp.None, 2015, https://doi.org/10.3389/fphar.2019.00824
  4. Chronic Hyperglycaemia Induced Alterations of Hepatic Stellate Cells Differ from the Effect of TGFB1, and Point toward Metabolic Stress vol.26, pp.1, 2015, https://doi.org/10.1007/s12253-018-0458-9
  5. LPS induces ALOX5 promoter activation and 5-lipoxygenase expression in human monocytic cells vol.154, pp.None, 2015, https://doi.org/10.1016/j.plefa.2020.102078
  6. Serum concentrations, pharmacokinetic/pharmacodynamic modeling, and effects of dexamethasone on inflammatory mediators following intravenous and oral administration to exercised horses vol.12, pp.8, 2015, https://doi.org/10.1002/dta.2862