Abstract
We investigated the effect of hydroxytyrosol (HT), a phenolic compound from virgin olive oil, on inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) expression in J774 murine macrophages stimulated with lipopolysaccharide (LPS). Incubation of cells with LPS caused an increase in iNOS and COX-2 mRNA and protein level as well as ROS generation, which was prevented by HT. In addition, HT blocked the activation of nuclear factor-κB (NF-κB), signal transducer and activator of transcription-1α (STAT-1α) and interferon regulatory factor-1 (IRF-1). These results, showing that HT down-regulates iNOS and COX-2 gene expression by preventing NF-κB, STAT-1α and IRF-1 activation mediated through LPS-induced ROS generation, suggest that it may represent a non-toxic agent for the control of pro-inflammatory genes.
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References
Boskou D (1996) Olive oil composition. In: Boskou D (ed) Olive oil chemistry and technology. AOCS, Champaign, pp 52–83
Carluccio MA, Siculella L, Ancora MA, Massaro M, Scoditti E, Storelli C, Visioli F, Distante A, De Caterina R (2003) Olive oil and red wine antioxidant polyphenols inhibit endothelial activation. Arterioscler Thromb Vasc Biol 23:622–629
Coussens LM, Werb Z (2002) Inflammation and cancer. Nature 420:860–867
D’Acquisto F, Ialenti A, Ianaro A, Di Vaio R, Carnuccio R (2000a) Local administration of transcription factor decoy oligonucleotides to nuclear factor-κB prevents carrageenin-induced inflammation in rat hind paw. Gene Ther 7:1731–1737
D’Acquisto F, Lanzotti V, Carnuccio R (2000b) Cyclolinteinone, a sesterterpene from Cacospongia Linteiformis, prevents inducible nitric oxide synthase and inducible cyclooxygenase protein expression by blocking nuclear factor-κB activation in J774 macrophages. Biochem J 346:793–798
D’Acquisto F, De Cristofaro F, Maiuri MC, Tajana G, Carnuccio R (2001) Protective role of nuclear factor kappa B against nitric oxide-induced apoptosis in J774 macrophages. Cell Death Differ 8:144–151
Deiana M, Aruoma OI, Bianchi MDLP, Spencer JPE, Kaur H, Halliwell B, Aeschbach R, Banni S, Dessi MA, Corongiu FP (1999) Inhibition of peroxynitrite dependent DNA base modification and tyrosine nitration by the extra virgin olive oil-derived antioxidant hydroxytyrosol. Free Radic Biol Med 26:762–769
De la Puerta R, Ruiz Gutierrez V, Hoult JRS (1999) Inhibition of leukocyte 5-lipoxygenase by phenolics from virgin olive oil. Biochem Pharmacol 57:445–449
De Lorgeril M, Salen P, Martin JL, Monjaud I, Delaye J, Mamelle N (1999) Mediterranean diet, traditional risk factors, and the rate of cardiovascular complications after myocardial infarction: final report of the Lyon Diet Heart Study. Circulation 99:779–785
Epinat JC, Gilmore TD (1999) Diverse agents act at multiple levels to inhibit the Rel/NF-κB signal transduction pathway. Oncogene 18:6896–6909
Faure V, Hecquet C, Courtois Y, Goureau O (1999) Role of interferon regulatory factor-1 and mitogen-activated protein kinase pathways in the induction of nitric oxide synthase-2 in retinal pigmented epithelial cells. J Biol Chem 274:4794–4800
Fletcher BS, Kujubu DA, Perrin DM, Herschman HR (1992) Structure of the mitogen-inducible TIS10 gene and demonstration that the TIS10-encoded protein is a functional prostaglandin G/H synthase. J Biol Chem 267:4338–4344
Gao J, Morrison DC, Parmely TJ, Russell SW, Murphy WJ (1997) An interferon-γ-activated site (GAS) is necessary for full expression of the mouse iNOS gene in response to interferon-γ and lipopolysaccharide. J Biol Chem 272:1226–1230
Hecker M, Preiß C, Klemm P, Busse R (1996) Inhibition by antioxidants of nitric oxide synthase expression in murine macrophages: role of nuclear factor κB and interferon regulatory factor 1. Br J Pharmacol 118:2178–2184
Hu X, Li W-P, Meng C, Ivashkiv LB (2003) Inhibition of IFN-γ signaling by glucocorticoids. J Immunol 170:4833–4839
Ialenti A, Grassia G, Di Meglio P, Maffia P, Di Rosa M, Ianaro A (2005) Mechanism of the anti-inflammatory effect of thiazolidinediones: relationship with the glucocorticoid pathway. Mol Pharmacol 67:1620–1628
Kamijo R, Harada H, Matsuyama T, Bosland M, Gerecitano J, Shapiro D, Le J, Koh SI, Kimura T, Green SJ, Mak TW, Taniguchi T, Vilček J (1994) Requirement for transcription factor IRF-1 in NO synthase induction in macrophages. Science 263:1612–1615
Keys A, Menotti A, Karvonene MJ, Aravanis C, Blackburn H, Buzina R, Djordjevic BS, Dontas AS, Fidanza F, Keys MH, Kromhout D, Nedeljkovic S, Punsar S, Seccareccia F, Toshima H (1986) The diet and 15-year death rate in the seven countries study. Am J Epidemiol 124:903–915
Kim HY, Park EJ, Joe E-H, Jou I (2003) Curcumin suppresses Janus Kinase-STAT inflammatory signalling through activation of Src Homology 2 domain-containing tyrosine phosphatase 2 in brain microglia. J Immunol 171:6072–6079
Kinugawa K-I, Shimizu T, Yao A, Kohmoto O, Serizawa T, Takahashi T (1997) Transcriptional regulation of inducible nitric oxide synthase in cultured neonatal rat cardiac myocytes. Circ Res 81:911–921
Kohyama N, Nagata T, Fujimoto S, Sekiya K (1997) Inhibition of arachidonate lipoxygenase activities by 2-(3,4-dihydroxyphenyl)ethanol, a phenolic compound from olives. Biosci Biotechnol Biochem 61:347–350
Kopp E, Ghosh S (1994) Inhibition of NF-kappaB by sodium salicylate and aspirin. Science 265:956–959
Kosaka T, Miyata A, Ihara H, Hara S, Sugimoto T, Takeda O, Takashi E, Tanabe T (1994) Characterization of the human gene (PTGS2) encoding prostaglandin-endoperoxide synthase 2. Eur J Biochem 221:889–897
Kröger A, Köster M, Schroeder K, Hansjörg H, Mueller PP (2002) Activities of IRF-1. J Interferon Cytokine Res 22:5–14
Lala PK, Chakraborty C (2001) Role of nitric oxide in carcinogenesis and tumour progression. Lancet 2:149–156
Lee WL, Henning B, Toborek M (2003) Redox-regulated mechanisms of IL-4-induced MCP-1 expression in human vascular endothelial cells. Am J Physiol Heart Circ Physiol 284:H185–H192
Lowenstein CJ, Alley EW, Raval P, Snowman AM, Snyder SH, Russell SW, Murphy WJ (1993) Macrophage nitric oxide synthase gene: two upstream regions mediate induction by interferon γ and lipopolysaccharide. Proc Natl Acad Sci U S A 90:9730–9734
Manna C, Galletti P, Cucciola V, Montedoro G, Zappia V (1999) Olive oil hydroxytyrosol protects human erythrocytes against oxidative damages. J Nutr Biochem 10:159–165
Martínez-Domínguez E, de la Puerta R, Ruiz-Gutiérrez V (2001) Protective effects upon experimental inflammation models of a polyphenol-supplemented virgin olive oil diet. Inflamm Res 50:102–106
Marx J (2004) Inflammation and cancer: the link grows stronger. Science 306:966–968
Ohmori Y, Hamilton TA (1993) Cooperative interaction between interferon (IFN) stimulus response element and κB sequence motifs controls IFNγ- and lipopolysaccharide-stimulated transcription from the murine IP-10 promoter. J Biol Chem 268:6677–6688
Ohmori Y, Hamilton TA (2001) Requirement for STAT1 in LPS-induced gene expression in macrophages. J Leukoc Biol 69:598–604
Owen RW, Giacosa A, Hull WE, Haubner R, Würtele G, Spiegelhalder B, Bartsch H (2000a) Olive-oil consumption and health: the possible role of antioxidants. Lancet 1:107–112
Owen RW, Mier W, Giacosa A, Hull WE, Spiegelhalder B, Bartsch H (2000b) Identification of lignans as major components in the phenolic fraction of olive oil. Clin Chem 46:976–988
Pahl HL (1999) Activators and target genes of Rel/NF-κB transcription factors. Oncogene 18:6853–6866
Petroni A, Blasevich M, Salami M, Papini N, Montedoro G, Galli G (1995) Inhibition of platelet aggregation and eicosanoid production by phenolic components of olive oil. Thromb Res 78:151–160
Ramana CV, Chatterjee-Kishore M, Nguyen H, Stark GR (2000) Complex role of Stat1 in regulating gene expression. Oncogene 19:2619–2627
Sacchi R, Paduano A, Fiore F, Della Medaglia D, Ambrosino ML, Medina I (2002) Partition behavior of virgin olive oil phenolic compounds in oil-brine mixtures during thermal processing for fish canning. J Agric Food Chem 50:2830–2835
Salami M, Galli C, De Angelis L, Visioli F (1995) Formation of F2-isoprostanes in oxidized low density lipoprotein: inhibitory effect of hydroxytyrosol. Pharmacol Res 31:275–279
Santamaria R, Irace C, Maffettone C, Festa M, Colonna A (2004) Induction of ferritin expression by oxalomalate. Biochim Biophys Acta 1691:151–159
Sirois J, Levy LO, Simmons DL, Richards JS (1993) Characterization and hormonal regulation of the promoter of the rat prostaglandin endoperoxide synthase 2 gene in granulosa cells. J Biol Chem 268:12199–12206
Tuck KL, Hayball PJ (2002) Major phenolic compounds in olive oil: metabolism and health effects. J Nutr Biochem 13(6):36–644
Visioli F, Poli A, Galli C (2002) Antioxidant and other biological activities of phenols from olives and olive oil. Med Res Rev 22(6):5–75
Zha S, Yegnasubramanian V, Nelson WG, Isaacs WB, De Marzo AM (2004) Cyclooxygenases in cancer: progress and perspective. Cancer Lett 215:1–20
Zhang S, Thomas K, Blanco JCG, Salkowski CA, Vogel SN (2002) The role of the interferon regulatory factors, IRF-1 and IRF-2, in LPS-induced cyclooxygenase-2 (COX-2) expression in vivo and in vitro. J Endotoxin Res 8:381–390
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This work was supported in part by Misura 3.17 P.O.R Campania and by the MURST-Cluster C08-A program.
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Maiuri, M.C., De Stefano, D., Di Meglio, P. et al. Hydroxytyrosol, a phenolic compound from virgin olive oil, prevents macrophage activation. Naunyn Schmied Arch Pharmacol 371, 457–465 (2005). https://doi.org/10.1007/s00210-005-1078-y
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DOI: https://doi.org/10.1007/s00210-005-1078-y