, Volume 35, Issue 3, pp 859–870 | Cite as

ICAM-1 and IL-8 Are Expressed by DEHP and Suppressed by Curcumin Through ERK and p38 MAPK in Human Umbilical Vein Endothelial Cells

  • Jia Wang
  • Sijun Dong


The present study aimed to determine whether curcumin isolated from the rhizome of Curcuma longa Linn could inhibit di-(2-ethylhexyl) phthalate (DEHP)-induced allergic inflammatory responses in human umbilical vein endothelial cells (HUVECs). We found that DEHP dose-dependently elevated adhesion molecule-1 (ICAM-1) protein level within 15–30 min, which was independent of de novo protein synthesis. And a late-phase induction of ICAM-1 was observed within 8 h treatment of DEHP via de novo protein synthesis through transcription and translation. DEHP also increased the expression of interleukin (IL)-8 in a time- and dose-dependent manner. Pretreatment with curcumin dose-dependently decreased DEHP-induced expression of ICAM-1 and IL-8 as well as phosphorylation of ERK1/2 and p38. Preincubation with ERK1/2 inhibitor (PD98059) or p38 inhibitor (SB203580) markedly blocked DEHP-stimulated activation of ICAM-1 and IL-8. We suggest that curcumin inhibits DEHP-induced expression of ICAM-1 and IL-8 through ERK and p38 MAPK signaling pathways in HUVECs and may contribute to ameliorate pathologies of DEHP-related allergic disorders.


curcumin di-(2-ethylhexyl) phthalate (DEHP) intercellular adhesion molecule-1 (ICAM-1) interleukin (IL)-8 



This investigation was supported by 100 Talents Program of Chinese Academy of Sciences (KZCX2-YW-BR-18) and the Science and Technology Planning Project of Xiamen City (3502Z20112019).


  1. 1.
    Lee, Y. L., W. H. Wang, C. W. Lu, Y. H. Lin, and B. F. Hwang. 2011. Effects of ambient air pollution on pulmonary function among schoolchildren. International Journal of Hygiene and Environmental Health. Google Scholar
  2. 2.
    Chalubinski, M., and M.L. Kowalski. 2006. Endocrine disrupters—potential modulators of the immune system and allergic response. Allergy 61: 1326–1335.PubMedCrossRefGoogle Scholar
  3. 3.
    Martino-Andrade, A.J., and I. Chahoud. 2010. Reproductive toxicity of phthalate esters. Molecular Nutrition & Food Research 54: 148–157.CrossRefGoogle Scholar
  4. 4.
    Rael, L.T., R. Bar-Or, D.R. Ambruso, C.W. Mains, D.S. Slone, M.L. Craun, and D. Bar-Or. 2009. Phthalate esters used as plasticizers in packed red blood cell storage bags may lead to progressive toxin exposure and the release of pro-inflammatory cytokines. Oxidative Medicine and Cellular Longevity 2: 166–171.PubMedCrossRefGoogle Scholar
  5. 5.
    Bornehag, C.G., J. Sundell, C.J. Weschler, T. Sigsgaard, B. Lundgren, M. Hasselgren, and L. Hagerhed-Engman. 2004. The association between asthma and allergic symptoms in children and phthalates in house dust: a nested case-control study. Environmental Health Perspectives 112: 1393–1397.PubMedCrossRefGoogle Scholar
  6. 6.
    Larsen, S.T., J.S. Hansen, E.W. Hansen, P.A. Clausen, and G.D. Nielsen. 2007. Airway inflammation and adjuvant effect after repeated airborne exposures to di-(2-ethylhexyl) phthalate and ovalbumin in BALB/c mice. Toxicology 235: 119–129.PubMedCrossRefGoogle Scholar
  7. 7.
    Oh, P.S., K. Lim, and K.T. Lim. 2010. Phytoglycoprotein (75 kDa) inhibits expression of interleukin-1 beta stimulated by DEHP in human mast cells. Cell Biochemistry and Function 28: 352–359.PubMedCrossRefGoogle Scholar
  8. 8.
    Yanagisawa, R., H. Takano, K. Inoue, E. Koike, K. Sadakane, and T. Ichinose. 2008. Effects of maternal exposure to di-(2-ethylhexyl) phthalate during fetal and/or neonatal periods on atopic dermatitis in male offspring. Environmental Health Perspectives 116: 1136–1141.PubMedCrossRefGoogle Scholar
  9. 9.
    Kostoryz, E.L., P.Y. Tong, A.F. Strautman, A.G. Glaros, J.D. Eick, and D.M. Yourtee. 2001. Effects of dental resins on TNF-alpha-induced ICAM-1 expression in endothelial cells. Journal of Dental Research 80: 1789–1792.PubMedCrossRefGoogle Scholar
  10. 10.
    Lee, M.F., N.M. Wang, S.W. Liu, S.J. Lin, and Y.H. Chen. 2010. Induction of interleukin 8 by American cockroach allergens from human airway epithelial cells via extracellular signal regulatory kinase and jun N-terminal kinase but not p38 mitogen-activated protein kinase. Annals of Allergy, Asthma & Immunology 105: 234–240.CrossRefGoogle Scholar
  11. 11.
    Mathew, R. 2010. Inflammation and pulmonary hypertension. Cardiology in Review 18: 67–72.PubMedCrossRefGoogle Scholar
  12. 12.
    Wu, W., V. Doreswamy, D. Diaz-Sanchez, J.M. Samet, M. Kesic, L. Dailey, W. Zhang, I. Jaspers, and D.B. Peden. 2011. GSTM1 modulation of IL-8 expression in human bronchial epithelial cells exposed to ozone. Free Radical Biology & Medicine 51: 522–529.CrossRefGoogle Scholar
  13. 13.
    Blau, H., K. Klein, I. Shalit, D. Halperin, and I. Fabian. 2007. Moxifloxacin but not ciprofloxacin or azithromycin selectively inhibits IL-8, IL-6, ERK1/2, JNK, and NF–kappaB activation in a cystic fibrosis epithelial cell line. American Journal of Physiology. Lung Cellular and Molecular Physiology 292: L343–L352.PubMedCrossRefGoogle Scholar
  14. 14.
    Chen, C.C., M.P. Chow, W.C. Huang, Y.C. Lin, and Y.J. Chang. 2004. Flavonoids inhibit tumor necrosis factor-alpha-induced up-regulation of intercellular adhesion molecule-1 (ICAM-1) in respiratory epithelial cells through activator protein-1 and nuclear factor-kappaB: structure–activity relationships. Molecular Pharmacology 66: 683–693.PubMedCrossRefGoogle Scholar
  15. 15.
    Babu, S.K., S.M. Puddicombe, H.H. Arshad, S.J. Wilson, J. Ward, N. Gozzard, G. Higgs, S.T. Holgate, and D.E. Davies. 2011. Tumor necrosis factor alpha (TNF-alpha) autoregulates its expression and induces adhesion molecule expression in asthma. Clinical Immunology 140: 18–25.PubMedCrossRefGoogle Scholar
  16. 16.
    Hsu, W.Y., Y.W. Chao, Y.L. Tsai, C.C. Lien, C.F. Chang, M.C. Deng, L.T. Ho, C.F. Kwok, and C.C. Juan. 2011. Resistin induces monocyte-endothelial cell adhesion by increasing ICAM-1 and VCAM-1 expression in endothelial cells via p38MAPK-dependent pathway. Journal of Cellular Physiology 226: 2181–2188.PubMedCrossRefGoogle Scholar
  17. 17.
    Yang, C.M., S.F. Luo, H.L. Hsieh, P.L. Chi, C.C. Lin, C.C. Wu, and L.D. Hsiao. 2010. Interleukin-1beta induces ICAM-1 expression enhancing leukocyte adhesion in human rheumatoid arthritis synovial fibroblasts: involvement of ERK, JNK, AP-1, and NF–kappaB. Journal of Cellular Physiology 224: 516–526.PubMedCrossRefGoogle Scholar
  18. 18.
    Zhang, X.D., J.F. Hou, X.J. Qin, W.L. Li, H.L. Chen, R. Liu, X. Liang, and C.X. Hai. 2010. Pentoxifylline inhibits intercellular adhesion molecule-1 (ICAM-1) and lung injury in experimental phosgene-exposure rats. Inhalation Toxicology 22: 889–895.PubMedCrossRefGoogle Scholar
  19. 19.
    Owens, E.O., M. Toborek, and B. Hennig. 2009. Flavonoids protect against intercellular adhesion molecule-1 induction by benzo[a]pyrene. Bulletin of Environmental Contamination and Toxicology 83: 4–7.PubMedCrossRefGoogle Scholar
  20. 20.
    Breen, L.T., P.E. McHugh, and B.P. Murphy. 2010. HUVEC ICAM-1 and VCAM-1 synthesis in response to potentially athero-prone and athero-protective mechanical and nicotine chemical stimuli. Annals of Biomedical Engineering 38: 1880–1892.PubMedCrossRefGoogle Scholar
  21. 21.
    Oesterling, E., M. Toborek, and B. Hennig. 2008. Benzo[a]pyrene induces intercellular adhesion molecule-1 through a caveolae and aryl hydrocarbon receptor mediated pathway. Toxicology and Applied Pharmacology 232: 309–316.PubMedCrossRefGoogle Scholar
  22. 22.
    Barton, R.W., R. Rothlein, J. Ksiazek, and C. Kennedy. 1989. The effect of anti-intercellular adhesion molecule-1 on phorbol-ester-induced rabbit lung inflammation. Journal of Immunology 143: 1278–1282.Google Scholar
  23. 23.
    Wu, S.J., K.W. Tam, Y.H. Tsai, C.C. Chang, and J.C. Chao. 2010. Curcumin and saikosaponin a inhibit chemical-induced liver inflammation and fibrosis in rats. The American Journal of Chinese Medicine 38: 99–111.PubMedCrossRefGoogle Scholar
  24. 24.
    Yadav, V.R., S. Prasad, R. Kannappan, J. Ravindran, M.M. Chaturvedi, L. Vaahtera, J. Parkkinen, and B.B. Aggarwal. 2010. Cyclodextrin-complexed curcumin exhibits anti-inflammatory and antiproliferative activities superior to those of curcumin through higher cellular uptake. Biochemical Pharmacology 80: 1021–1032.PubMedCrossRefGoogle Scholar
  25. 25.
    Bian, Z.M., V.M. Elner, A. Yoshida, S.L. Kunkel, and S.G. Elner. 2001. Signaling pathways for glycated human serum albumin-induced IL-8 and MCP-1 secretion in human RPE cells. Investigative Ophthalmology & Visual Science 42: 1660–1668.Google Scholar
  26. 26.
    Lim, J.H., and T.K. Kwon. 2010. Curcumin inhibits phorbol myristate acetate (PMA)-induced MCP-1 expression by inhibiting ERK and NF-kappaB transcriptional activity. Food and Chemical Toxicology 48: 47–52.PubMedCrossRefGoogle Scholar
  27. 27.
    Song, W.B., Y.Y. Wang, F.S. Meng, Q.H. Zhang, J.Y. Zeng, L.P. Xiao, X.P. Yu, D.D. Peng, L. Su, B. Xiao, and Z.S. Zhang. 2010. Curcumin protects intestinal mucosal barrier function of rat enteritis via activation of MKP-1 and attenuation of p38 and NF-kappaB activation. PloS One 5: e12969.PubMedCrossRefGoogle Scholar
  28. 28.
    Inoue, K., M. Kobayashi, K. Yano, M. Miura, A. Izumi, C. Mataki, T. Doi, T. Hamakubo, P.C. Reid, D.A. Hume, M. Yoshida, W.C. Aird, T. Kodama, and T. Minami. 2006. Histone deacetylase inhibitor reduces monocyte adhesion to endothelium through the suppression of vascular cell adhesion molecule-1 expression. Arteriosclerosis, Thrombosis, and Vascular Biology 26: 2652–2659.PubMedCrossRefGoogle Scholar
  29. 29.
    Volanti, C., G. Gloire, A. Vanderplasschen, N. Jacobs, Y. Habraken, and J. Piette. 2004. Downregulation of ICAM-1 and VCAM-1 expression in endothelial cells treated by photodynamic therapy. Oncogene 23: 8649–8658.PubMedCrossRefGoogle Scholar
  30. 30.
    Muro, S., E.H. Schuchman, and V.R. Muzykantov. 2006. Lysosomal enzyme delivery by ICAM-1-targeted nanocarriers bypassing glycosylation- and clathrin-dependent endocytosis. Molecular Therapy 13: 135–141.PubMedCrossRefGoogle Scholar
  31. 31.
    Muro, S., M. Mateescu, C. Gajewski, M. Robinson, V.R. Muzykantov, and M. Koval. 2006. Control of intracellular trafficking of ICAM-1-targeted nanocarriers by endothelial Na+/H + exchanger proteins. American Journal of Physiology. Lung Cellular and Molecular Physiology 290: L809–L817.PubMedCrossRefGoogle Scholar
  32. 32.
    Hau, C. S., Y. Tada, S. Shibata, H. Uratsuji, Y. Asano, M. Sugaya, T. Kadono, N. Kanda, S. Watanabe, K. Tamaki, and S. Sato. 2011. High calcium, ATP, and poly(I:C) augment the immune response to beta-glucan in normal human epidermal keratinocytes. Journal of Investigative Dermatology. doi: 10.1038/jid.2011.201
  33. 33.
    Lee, J., P.S. Oh, and K.T. Lim. 2011. Allergy-related cytokines (IL-4 and TNF-alpha) are induced by di(2-ethylhexyl) phthalate and attenuated by plant-originated glycoprotein (75 kDa) in HMC-1 cells. Environmental Toxicology 26: 364–372.PubMedCrossRefGoogle Scholar
  34. 34.
    Maruyama, T., T. Shiba, H. Iizuka, T. Matsuda, K. Kurohane, and Y. Imai. 2007. Effects of phthalate esters on dendritic cell subsets and interleukin-4 production in fluorescein isothiocyanate-induced contact hypersensitivity. Microbiology and Immunology 51: 321–326.PubMedGoogle Scholar
  35. 35.
    Yang, Y.J., Y.C. Hong, S.Y. Oh, M.S. Park, H. Kim, J.H. Leem, and E.H. Ha. 2009. Bisphenol A exposure is associated with oxidative stress and inflammation in postmenopausal women. Environmental Research 109: 797–801.PubMedCrossRefGoogle Scholar
  36. 36.
    Oh, P. S., and K. T. Lim. 2010. IgE, COX-2, and IL-4 are expressed by DEHP through p38 MAPK and suppressed by plant glycoprotein (75 kDa) in ICR mice. Inflammation (in press)Google Scholar
  37. 37.
    Yamagishi, S., Y. Inagaki, K. Nakamura, and T. Imaizumi. 2004. Azelnidipine, a newly developed long-acting calcium antagonist, inhibits tumor necrosis factor-alpha-induced interleukin-8 expression in endothelial cells through its anti-oxidative properties. Journal of Cardiovascular Pharmacology 43: 724–730.PubMedCrossRefGoogle Scholar
  38. 38.
    Chang, Y.L., C.L. Chen, C.L. Kuo, B.C. Chen, and J.S. You. 2010. Glycyrrhetinic acid inhibits ICAM-1 expression via blocking JNK and NF-kappaB pathways in TNF-alpha-activated endothelial cells. Acta Pharmacologica Sinica 31: 546–553.PubMedCrossRefGoogle Scholar
  39. 39.
    Pepys, J., and B.J. Hutchcroft. 1975. American Review of Respiratory Disease 112: 829–859.PubMedGoogle Scholar
  40. 40.
    Kim, Y.S., Y. Ahn, M.H. Hong, S.Y. Joo, K.H. Kim, I.S. Sohn, H.W. Park, Y.J. Hong, J.H. Kim, W. Kim, M.H. Jeong, J.G. Cho, J.C. Park, and J.C. Kang. 2007. Curcumin attenuates inflammatory responses of TNF-alpha-stimulated human endothelial cells. Journal of Cardiovascular Pharmacology 50: 41–49.PubMedCrossRefGoogle Scholar
  41. 41.
    Lin, F.S., C.C. Lin, C.S. Chien, S.F. Luo, and C.M. Yang. 2005. Involvement of p42/p44 MAPK, JNK, and NF-kappaB in IL-1beta-induced ICAM-1 expression in human pulmonary epithelial cells. Journal of Cellular Physiology 202: 464–473.PubMedCrossRefGoogle Scholar
  42. 42.
    Martins, J.O., B.M. Wittlin, D.B. Anger, D.O. Martins, P. Sannomiya, and S. Jancar. 2010. Early phase of allergic airway inflammation in diabetic rats: role of insulin on the signaling pathways and mediators. Cellular Physiology and Biochemistry 26: 739–748.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.Institute of Urban EnvironmentChinese Academy of SciencesXiamenPeople’s Republic of China

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