Abstract
Toll-like receptors (TLRs) are major receptors that mediate the innate immune and inflammatory responses, of which TLR4 has been found most closely related to human atherosclerosis. After ligands are polymerized and activated by TLR, the mitogen-activated protein kinase and nuclear factor-κB (NF-κB) pathways are activated, leading to promotion of NF-κB–regulated transcription of inflammatory factors, thus playing a role in the physiological and pathological processes in atherosclerosis. Oxidized lipoproteins or their components, oxidized lipids, have been confirmed as endogenous TLR receptors. Lysophosphatidic acid (LPA) is an active component of low-density lipoprotein that induces vascular endothelial lesions. However, the mechanism of the TLR4/NF-κB signaling system involved in LPA-induced atherosclerosis has not been fully elucidated. In this study, we investigated the effects of LPA on TLR4 expression, nuclear translocation of NF-κB p65 subunit, and changes in the cytokine tumor necrosis factor α (TNF-α) in human THP-1 cells. LPA upregulated expression of the TLR4 mRNA and protein in THP-1 cells in a dose- and time-dependent manner, induced NF-κB p65 activation synchronously in THP-1 cells, and increased TNF-α secretion. After TLR4 was blocked using TLR4 monoclonal antibody, NF-κB p65 expression and TNF-α secretion were inhibited significantly. These data suggest that LPA can significantly upregulate TLR4 expression and promote NF-κB activation and proinflammatory cytokine secretion in THP-1 cells; it is possible that the TLR4/NF-κB signaling pathway mediates the atherogenic effect of LPA.
Similar content being viewed by others
Abbreviations
- TLRs:
-
Toll-like receptors
- NF-κB:
-
Nuclear factor-κB
- LPA:
-
Lysophosphatidic acid
- TNF-α:
-
Tumor necrosis factor α
References
Raveendran VV, Tan X, Sweeney ME, Levant B, Slusser J, Stechschulte DJ, Dileepan KN (2011) Lipopolysaccharide induces H1 receptor expression and enhances histamine responsiveness in human coronary artery endothelial cells. Immunology 13:578–588
Janeway CA Jr, Medzhitov R (2002) Innate immune recognition. Annu Rev Immunol 20:197–216
Dunzendorfer S, Lee HK, Soldau K, Tobias PS (2004) Toll-like receptor 4 functions intracellularly in human coronary artery endothelial cells: roles of LBP and sCD14 in mediating LPS responses. FASEB J 18:1117–1119
Balogh S, Kiss I, Csaszar A (2009) Toll-like receptors: link between “danger” ligands and plaque instability. Curr Drug Targets 10:513–518
Xu XH, Shah PK, Faure E, Equils O, Thomas L, Fishbein MC, Luthringer D, Xu XP, Rajavashisth TB, Yano J, Kaul S, Arditi M (2001) Toll-like receptor-4 is expressed by macrophages in murine and human lipid-rich atherosclerotic plaques and upregulated by oxidized LDL. Circulation 104:3103–3108
Edfeldt K, Swedenborg J, Hansson GK, Yan ZQ (2002) Expression of toll-like receptors in human atherosclerotic lesions: a possible pathway for plaque activation. Circulation 105:1158–1161
Clària J (2006) Regulation of cell proliferation and apoptosis by bioactive lipid mediators. Recent Pat Anticancer Drug Discov 1:369–382
Tigyi G (2001) Physiological responses to lysophosphatidic acid and related Glycerol-phospholipids. Prostaglandins Other Lipid Mediat 64:47–62
Siess W, Tigyi G (2004) Thrombogenic and atherogenic activities of lysophosphatidic acid. J Cell Biochem 92:1086–1094
Ai S, Kuzuya M, Koike T, Asai T, Kanda S, Maeda K, Shibata T, Iguchi A (2001) Rho–Rho kinase is involved in smooth muscle cell migration through myosin light chain phosphorylation-dependent and -independent pathways. Atherosclerosis 155:321–327
Newton HJ, Pearson JS, Badea L, Kelly M, Lucas M, Holloway G, Wagstaff KM, Dunstone MA, Sloan J, Whisstock JC, Kaper JB, Robins-Browne RM, Jans DA, Frankel G, Phillips AD, Coulson BS, Hartland EL (2010) The type III effectors NleE and NleB from enteropathogenic E. coli and OspZ from Shigella block nuclear translocation of NF-kappaB p65. PLoS Pathog 6:e1000898
Banchereau J, Steinman RM (1998) Dendritic cells and control of immunity. Nature 392:245–252
Libby P (2002) Inflammation in atherosclerosis. Nature 420:868–874
Hansson GK, Libby P, Schonbeck U, Yan ZQ (2002) Innate and adaptive immunity in the pathogenesis of atherosclerosis. Circ Res 91:281–291
Schnare M, Barton GM, Holt AC, Takeda K, Akira S, Medzhitov R (2001) Toll-like receptors control activation of adaptive immune responses. Nat Immunol 2:947–950
Michelsen KS, Wong MH, Shah PK, Zhang W, Yano J, Doherty TM, Akira S, Rajavashisth TB, Arditi M (2004) Lack of Toll-like receptor 4 or myeloid differentiation factor 88 reduces atherosclerosis and alters plaque phenotype in mice deficient in apolipoprotein E. Proc Natl Acad Sci U.S.A. 101:10679–10684
Akashi S, Shimazu R, Ogata H, Nagai Y, Takeda K, Kimoto M, Miyake K (2000) Cutting edge: cell surface expression and lipopolysaccharide signaling via the toll-like receptor 4-MD-2 complex on mouse peritoneal macrophages. J Immunol 164:3471–3475
Ueta M, Nochi T, Jang MH, Park EJ, Igarashi O, Hino A, Kawasaki S, Shikina T, Hiroi T, Kinoshita S, Kiyono H (2004) Intracellularly expressed TLR2s and TLR4s contribution to an immunosilent environment at the ocular mucosal epithelium. J Immunol. 173:3337–3347
Biragyn A, Ruffini PA, Leifer CA, Klyushnenkova E, Shakhov A, Chertov O, Shirakawa AK, Farber JM, Segal DM, Oppenheim JJ, Kwak LW (2002) Toll-like receptor 4-dependent activation of dendritic cells by beta-defensin 2. Science 298:1025–1029
Mullick AE, Soldau K, Kiosses WB, Bell TA 3rd, Tobias PS, Curtiss LK (2008) Increased endothelial expression of Toll-like receptor 2 at sites of disturbed blood flow exacerbates early atherogenic events. J Exp Med 205:373–383
Mullick AE, Tobias PS, Curtiss LK (2005) Modulation of atherosclerosis in mice by Toll-like receptor 2. J Clin Invest 115:3149–3156
Hollestelle SC, De Vries MR, Van Keulen JK, Schoneveld AH, Vink A, Strijder CF, Van Middelaar BJ, Pasterkamp G, Quax PH, De Kleijn DP (2004) Toll-like receptor 4 is involved in outward arterial remodeling. Circulation 109:393–398
Knuefermann P, Nemoto S, Baumgarten G, Misra A, Sivasubramanian N, Carabello BA, Vallejo JG (2002) Cardiac inflammation and innate immunity in septic shock:is there a role for Toll-like receptors? Chest 121:1329–1336
Acknowledgments
This work was supported by a Grant from the Nature Science Foundation of Fujian province, China (No.2010D010).
Author information
Authors and Affiliations
Corresponding authors
Additional information
Bo Yang, Zhibin Zhou, Xiaohao Li and Jianping Niu contributed to the work equally and should be regarded as co-first authors.
Rights and permissions
About this article
Cite this article
Yang, B., Zhou, Z., Li, X. et al. The effect of lysophosphatidic acid on Toll-like receptor 4 expression and the nuclear factor-κB signaling pathway in THP-1 cells. Mol Cell Biochem 422, 41–49 (2016). https://doi.org/10.1007/s11010-016-2804-0
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11010-016-2804-0