Abstract
Objective
The aim of this study was to investigate the inhibitory effect of geniposide on lipopolysaccharide (LPS)-induced interleukin-6 (IL-6) and interleukin-8 (IL-8) production in human umbilical vein endothelial cells (HUVECs).
Materials and methods
Primary HUVECs were used. The mRNA/protein levels of IL-6 and IL-8 was determined by reverse transcription-polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA). LPS-induced HUVEC migration and adhesion of monocytes to HUVECs were studied by monolayer wound healing experiments and monocytic cell adhesion assay, respectively. Expression of nuclear factor κB (NF-κB), inhibitory factor κB-α (IκB-α), p38 mitogen-activated protein kinase (MAPK) and ERK1/2 were determined by Western blot analysis.
Results
Geniposide effectively inhibited LPS-induced expression of IL-6 and IL-8 in HUVECs at the transcription and translation levels. Additionally, geniposide suppressed LPS-induced HUVEC migration and U937 monocyte adhesion to HUVECs. Signal transduction studies indicate that geniposide blocked the activation of NF-κB, degradation of IκB-α, and phosphorylation of p38 MAPK and ERK1/2 in HUVECs challenged by LPS.
Conclusion
The results show that geniposide can inhibit LPS-induced IL-6 and IL-8 production in HUVECs by blocking p38 MAPK and ERK1/2 signaling pathways.
Similar content being viewed by others
References
Tuo QH, Wang C, Yan FX, Liao DF. MAPK pathway mediates the protective effects of onychin on oxidative stress-induced apoptosis in ECV304 endothelial cells. Life Sci. 2004;76:487–97.
Altman R, Motton DD, Kota RS, Rutledge JC. Inhibition of vascular inflammation by dehydroepiandrosterone sulfate in human aortic endothelial cells: roles of PPARalpha and NF-kappaB. Vascul Pharmacol. 2008;48:76–84.
Li HL, He Y, Zhang JJ, Sun SH, Sun BG. Lipopolysaccharide regulates toll-like receptor 4 expression in human aortic smooth muscle cells. Cell Biol Int. 2007;31:831–5.
Anand AR, Cucchiarini M, Terwilliger EF, Ganju RK. The tyrosine kinase Pyk2 mediates lipopolysaccharide-induced IL-8 expression in human endothelial cells. J Immunol. 2008;180:5636–44.
Weglarz L, Dzierzewicz Z, Skop B, Orchel A, Parfiniewicz B, Wiśniowska B, et al. Desulfovibrio desulfuricans lipopolysaccharides induce endothelial cell IL-6 and IL-8 secretion and E-selectin and VCAM-1 expression. Cell Mol Biol Lett. 2003;8:991–1003.
Hashimoto S, Gon Y, Matsumoto K, Maruoka S, Takeshita I, Hayashi S, et al. Selective inhibitor of p38 mitogen-activated protein kinase inhibits lipopolysaccharide-induced interleukin-8 expression in human pulmonary vascular endothelial cells. J Pharmacol Exp Ther. 2000;293:370–5.
Mantovani A, Bussolino F, Introna M. Cytokine regulation of endothelial cell function: from molecular level to the bedside. Immunol Today. 1997;18:231–40.
Chen QC, Zhang WY, Kim H, Lee IS, Ding Y, Youn UJ et al. Effects of gardeniae fructus extract and geniposide on promoting ligament cell proliferation and collagen synthesis. Phytother Res (in press) 2009. doi: 10.1002/ptr.2839.
Liu JH, Yin F, Guo LX, Deng XH, Hu YH. Neuroprotection of geniposide against hydrogen peroxide induced PC12 cells injury: involvement of PI3 kinase signal pathway. Acta Pharmacol Sin. 2009;30:159–65.
Liu J, Yin F, Zheng X, Jing J, Hu Y. Geniposide, a novel agonist for GLP-1 receptor, prevents PC12 cells from oxidative damage via MAP kinase pathway. Neurochem Int. 2007;51:361–9.
Wang SW, Lai CY, Wang CJ. Inhibitory effect of geniposide on aflatoxin B1-induced DNA repair synthesis in primary cultured rat hepatocytes. Cancer Lett. 1992;65:133–7.
Peng CH, Huang CN, Hsu SP, Wang CJ. Penta-acetyl geniposide-induced apoptosis involving transcription of NGF/p75 via MAPK-mediated AP-1 activation in C6 glioma cells. Toxicology. 2007;238:130–9.
Liaw J, Chao YC. Effect of in vitro and in vivo aerosolized treatment with geniposide on tracheal permeability in ovalbumin-induced guinea pigs. Eur J Pharmacol. 2001;433:115–21.
Wu SY, Wang GF, Liu ZQ, Rao JJ, Lü L, Xu W, et al. Effect of geniposide, a hypoglycemic glucoside, on hepatic regulating enzymes in diabetic mice induced by a high-fat diet and streptozotocin. Acta Pharmacol Sin. 2009;30:202–8.
Suzuki Y, Kondo K, Ikeda Y, Umemura K. Antithrombotic effect of geniposide and genipin in the mouse thrombosis model. Planta Med. 2001;67:807–10.
Koo HJ, Lee S, Shin KH, Kim BC, Lim CJ, Park EH. Geniposide, an anti-angiogenic compound from the fruits of Gardenia jasminoides. Planta Med. 2004;70:467–9.
Lee P, Lee J, Choi SY, Lee SE, Lee S, Son D. Geniposide from Gardenia jasminoides attenuates neuronal cell death in oxygen and glucose deprivation-exposed rat hippocampal slice culture. Biol Pharm Bull. 2006;29:174–6.
Unger RE, Krump-Konvalinkova V, Peters K, Kirkpatrick CJ. In vitro expression of the endothelial phenotype: comparative study of primary isolated cells and cell lines, including the novel cell line HPMEC-ST1.6R. Microvasc Res. 2002;64:384–97.
Shen J, DiCorleto PE. ADP stimulates human endothelial cell migration via P2Y1 nucleotide receptor-mediated mitogen-activated protein kinase pathways. Circ Res. 2008;102:448–56.
Galley HF, Dhillon JK, Paterson RL, Webster NR. Effect of ciprofloxacin on the activation of the transcription factors nuclear factor kappaB, activator protein-1 and nuclear factor-interleukin-6, and interleukin-6 and interleukin-8 mRNA expression in a human endothelial cell line. Clin Sci (Lond). 2000;99:405–10.
Ozes ON, Mayo LD, Gustin JA, Pfeffer SR, Pfeffer LM, Donner DB. NF-kappaB activation by tumour necrosis factor requires the Akt serine–threonine kinase. Nature. 1999;401:82–5.
Hippenstiel S, Soeth S, Kellas B, Fuhrmann O, Seybold J, Krüll M, et al. Rho proteins and the p38-MAPK pathway are important mediators for LPS-induced interleukin-8 expression in human endothelial cells. Blood. 2000;95:3044–51.
Rietschel ET, Brade H. Bacterial endotoxins. Sci Am. 1992;267:54–61.
Endo S, Inada K, Inoue Y, Kuwata Y, Suzuki M, Yamashita H, et al. Two types of septic shock classified by the plasma levels of cytokines and endotoxin. Circ Shock. 1992;38:264–74.
Desai TR, Leeper NJ, Hynes KL, Gewertz BL. Interleukin-6 causes endothelial barrier dysfunction via the protein kinase C pathway. J Surg Res. 2002;104:118–23.
Noda A, Kinoshita K, Sakurai A, Matsumoto T, Mugishima H, Tanjoh K. Hyperglycemia and lipopolysaccharide decrease depression effect of interleukin 8 production by hypothermia: an experimental study with endothelial cells. Intensive Care Med. 2008;34:109–15.
Oh GS, Pae HO, Choi BM, Lee HS, Kim IK, Yun YG, et al. Penta-O-galloyl-beta-d-glucose inhibits phorbol myristate acetate-induced interleukin-8 [correction of intereukin-8] gene expression in human monocytic U937 cells through its inactivation of nuclear factor-kappaB. Int Immunopharmacol. 2004;4:377–86.
Kaplanski G, Teysseire N, Farnarier C, Kaplanski S, Lissitzky JC, Durand JM, et al. IL-6 and IL-8 production from cultured human endothelial cells stimulated by infection with Rickettsia conorii via a cell-associated IL-1 alpha-dependent pathway. J Clin Invest. 1995;96:2839–44.
Koo HJ, Lim KH, Jung HJ, Park EH. Anti-inflammatory evaluation of gardenia extract, geniposide and genipin. J Ethnopharmacol. 2006;103:496–500.
Malinda KM, Sidhu GS, Banaudha KK, Gaddipati JP, Maheshwari RK, Goldstein AL, et al. Thymosin alpha 1 stimulates endothelial cell migration, angiogenesis, and wound healing. J Immunol. 1998;160:1001–6.
Thevenard J, Ramont L, Devy J, Brassart B, Dupont-Deshorgue A, Floquet N et al. The YSNSG cyclopeptide derived from tumstatin inhibits tumor angiogenesis by down-regulating endothelial cell migration. Int J Cancer (in press) 2009. doi:10.1002/ijc.24688.
Liu J, Li X, Yue Y, Li J, He T, He Y. The inhibitory effect of quercetin on IL-6 production by LPS-stimulated neutrophils. Cell Mol Immunol. 2005;2:455–60.
Sun DI, Nizamutdinova IT, Kim YM, Cai XF, Lee JJ, Kang SS, et al. Bisacurone inhibits adhesion of inflammatory monocytes or cancer cells to endothelial cells through down-regulation of VCAM-1 expression. Int Immunopharmacol. 2008;8:1272–81.
Ponce C, Torres M, Galleguillos C, Sovino H, Boric MA, Fuentes A, et al. Nuclear factor kappaB pathway and interleukin-6 are affected in eutopic endometrium of women with endometriosis. Reproduction. 2009;137:727–37.
Huang HP, Shih YW, Wu CH, Lai PJ, Hung CN, Wang CJ. Inhibitory effect of penta-acetyl geniposide on C6 glioma cells metastasis by inhibiting matrix metalloproteinase-2 expression involved in both the PI3K and ERK signaling pathways. Chem Biol Interact. 2009;181:8–14.
Johnson GL, Lapadat R. Mitogen-activated protein kinase pathways mediated by ERK, JNK, and p38 protein kinases. Science. 2002;298:1911–2.
Nizamutdinova IT, Oh HM, Min YN, Park SH, Lee MJ, Kim JS, et al. Paeonol suppresses intercellular adhesion molecule-1 expression in tumor necrosis factor-α-stimulated human umbilical vein endothelial cells by blocking p38, ERK and nuclear factor-κB signaling pathways. Int Immunopharmacol. 2007;7:343–50.
Li XY, He JL, Liu HT, Li WM, Yu C. Tetramethylpyrazine suppresses interleukin-8 expression in LPS-stimulated human umbilical vein endothelial cell by blocking ERK, p38 and nulear factor-kappaB signaling pathways. J Ethnopharmacol. 2009;125:83–9.
Acknowledgments
This work was supported by the Natural Science Fund of Chongqing, China (KJ070304), and by the Science Fund of Chongqing Medical University (XBED200806).
Author information
Authors and Affiliations
Corresponding author
Additional information
Responsible Editor: M. Katori.
Rights and permissions
About this article
Cite this article
Liu, HT., He, JL., Li, WM. et al. Geniposide inhibits interleukin-6 and interleukin-8 production in lipopolysaccharide-induced human umbilical vein endothelial cells by blocking p38 and ERK1/2 signaling pathways. Inflamm. Res. 59, 451–461 (2010). https://doi.org/10.1007/s00011-009-0118-3
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00011-009-0118-3