Skip to main content
NCBI home page
Mediators of Inflammation logoLink to Mediators of Inflammation
. 2003 Feb;12(1):29–35. doi: 10.1080/0962935031000096962

Upregulation of expression of the chemokine receptor CCR5 by hydrogen peroxide in human monocytes.

Geneviève Lehoux 1, Christian Le Gouill 1, Jana Stankova 1, Marek Rola-Pleszczynski 1
PMCID: PMC1781589  PMID: 12745546

Abstract

The objective of this study was to test the hypothesis that an oxidative stress can serve as a signal to regulate the expression of CCR5. When human monocytes were exposed to graded concentration of hydrogen peroxide (H(2)O(2)), CCR5 mRNA levels increased maximally at 4 h of exposure to 200 microM of H(2)O(2) and decreased by 24 h of treatment. Pretreatment of monocytes with the NF-kappaB inhibitor BAY 11-8072 blocked the H(2)O(2)-induced augmentation of CCR5 mRNA expression, suggesting a role for this transcription factor in the regulation of CCR5 expression. CCR5 protein expression on the plasma membrane was also increased by treatment with H(2)O(2,) as assessed by flow cytometry. This was accompanied by enhanced responsiveness of H(2)O(2)-pretreated monocytes to the CCR5 ligand MIP-1beta in terms of chemotaxis and c-fos gene activation. Our results suggest that oxidative stress may indeed modulate the expression of chemokine receptors and thus contribute to regulation of the inflammatory process.

Full Text

The Full Text of this article is available as a PDF (397.0 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Allen J. F. Redox control of transcription: sensors, response regulators, activators and repressors. FEBS Lett. 1993 Oct 18;332(3):203–207. doi: 10.1016/0014-5793(93)80631-4. [DOI] [PubMed] [Google Scholar]
  2. Aruoma O. I., Halliwell B., Hoey B. M., Butler J. The antioxidant action of N-acetylcysteine: its reaction with hydrogen peroxide, hydroxyl radical, superoxide, and hypochlorous acid. Free Radic Biol Med. 1989;6(6):593–597. doi: 10.1016/0891-5849(89)90066-x. [DOI] [PubMed] [Google Scholar]
  3. Babior B. M., Kipnes R. S., Curnutte J. T. Biological defense mechanisms. The production by leukocytes of superoxide, a potential bactericidal agent. J Clin Invest. 1973 Mar;52(3):741–744. doi: 10.1172/JCI107236. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Baehner R. L., Nathan D. G., Castle W. B. Oxidant injury of caucasian glucose-6-phosphate dehydrogenase-deficient red blood cells by phagocytosing leukocytes during infection. J Clin Invest. 1971 Dec;50(12):2466–2473. doi: 10.1172/JCI106747. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Baeuerle P. A., Baltimore D. NF-kappa B: ten years after. Cell. 1996 Oct 4;87(1):13–20. doi: 10.1016/s0092-8674(00)81318-5. [DOI] [PubMed] [Google Scholar]
  6. Baeuerle P. A. IkappaB-NF-kappaB structures: at the interface of inflammation control. Cell. 1998 Dec 11;95(6):729–731. doi: 10.1016/s0092-8674(00)81694-3. [DOI] [PubMed] [Google Scholar]
  7. Baeuerle P. A., Rupec R. A., Pahl H. L. Reactive oxygen intermediates as second messengers of a general pathogen response. Pathol Biol (Paris) 1996 Jan;44(1):29–35. [PubMed] [Google Scholar]
  8. Baldwin A. S., Jr The NF-kappa B and I kappa B proteins: new discoveries and insights. Annu Rev Immunol. 1996;14:649–683. doi: 10.1146/annurev.immunol.14.1.649. [DOI] [PubMed] [Google Scholar]
  9. Bandres J. C., Trial J., Musher D. M., Rossen R. D. Increased phagocytosis and generation of reactive oxygen products by neutrophils and monocytes of men with stage 1 human immunodeficiency virus infection. J Infect Dis. 1993 Jul;168(1):75–83. doi: 10.1093/infdis/168.1.75. [DOI] [PubMed] [Google Scholar]
  10. Barnes P. J., Karin M. Nuclear factor-kappaB: a pivotal transcription factor in chronic inflammatory diseases. N Engl J Med. 1997 Apr 10;336(15):1066–1071. doi: 10.1056/NEJM199704103361506. [DOI] [PubMed] [Google Scholar]
  11. Bell A. L., Markey G. M., Alexander H. D., Morris T. C., McMillan S. A., McNally J. A. Myeloperoxidase deficiency in a patient with rheumatoid arthritis: oxygenation and radical activity by phagocytic cells. Br J Rheumatol. 1993 Feb;32(2):162–165. doi: 10.1093/rheumatology/32.2.162. [DOI] [PubMed] [Google Scholar]
  12. Brown K., Gerstberger S., Carlson L., Franzoso G., Siebenlist U. Control of I kappa B-alpha proteolysis by site-specific, signal-induced phosphorylation. Science. 1995 Mar 10;267(5203):1485–1488. doi: 10.1126/science.7878466. [DOI] [PubMed] [Google Scholar]
  13. Buttke T. M., Sandstrom P. A. Oxidative stress as a mediator of apoptosis. Immunol Today. 1994 Jan;15(1):7–10. doi: 10.1016/0167-5699(94)90018-3. [DOI] [PubMed] [Google Scholar]
  14. Chapple I. L. Reactive oxygen species and antioxidants in inflammatory diseases. J Clin Periodontol. 1997 May;24(5):287–296. doi: 10.1111/j.1600-051x.1997.tb00760.x. [DOI] [PubMed] [Google Scholar]
  15. Chomczynski P., Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987 Apr;162(1):156–159. doi: 10.1006/abio.1987.9999. [DOI] [PubMed] [Google Scholar]
  16. Devary Y., Gottlieb R. A., Lau L. F., Karin M. Rapid and preferential activation of the c-jun gene during the mammalian UV response. Mol Cell Biol. 1991 May;11(5):2804–2811. doi: 10.1128/mcb.11.5.2804. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Finkel T. Oxygen radicals and signaling. Curr Opin Cell Biol. 1998 Apr;10(2):248–253. doi: 10.1016/s0955-0674(98)80147-6. [DOI] [PubMed] [Google Scholar]
  18. Finkel T. Signal transduction by reactive oxygen species in non-phagocytic cells. J Leukoc Biol. 1999 Mar;65(3):337–340. doi: 10.1002/jlb.65.3.337. [DOI] [PubMed] [Google Scholar]
  19. Hall I. P., Wheatley A., Christie G., McDougall C., Hubbard R., Helms P. J. Association of CCR5 delta32 with reduced risk of asthma. Lancet. 1999 Oct 9;354(9186):1264–1265. doi: 10.1016/s0140-6736(99)03425-x. [DOI] [PubMed] [Google Scholar]
  20. Kamata H., Hirata H. Redox regulation of cellular signalling. Cell Signal. 1999 Jan;11(1):1–14. doi: 10.1016/s0898-6568(98)00037-0. [DOI] [PubMed] [Google Scholar]
  21. Karpus W. J., Lukacs N. W., McRae B. L., Strieter R. M., Kunkel S. L., Miller S. D. An important role for the chemokine macrophage inflammatory protein-1 alpha in the pathogenesis of the T cell-mediated autoimmune disease, experimental autoimmune encephalomyelitis. J Immunol. 1995 Nov 15;155(10):5003–5010. [PubMed] [Google Scholar]
  22. Kretz-Remy C., Mehlen P., Mirault M. E., Arrigo A. P. Inhibition of I kappa B-alpha phosphorylation and degradation and subsequent NF-kappa B activation by glutathione peroxidase overexpression. J Cell Biol. 1996 Jun;133(5):1083–1093. doi: 10.1083/jcb.133.5.1083. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Kunkel S. L., Standiford T., Kasahara K., Strieter R. M. Interleukin-8 (IL-8): the major neutrophil chemotactic factor in the lung. Exp Lung Res. 1991 Jan-Feb;17(1):17–23. doi: 10.3109/01902149109063278. [DOI] [PubMed] [Google Scholar]
  24. Lee J. S., Kahlon S. S., Culbreth R., Cooper A. D., Jr Modulation of monocyte chemokine production and nuclear factor kappa B activity by oxidants. J Interferon Cytokine Res. 1999 Jul;19(7):761–767. doi: 10.1089/107999099313613. [DOI] [PubMed] [Google Scholar]
  25. Liu R., Zhao X., Gurney T. A., Landau N. R. Functional analysis of the proximal CCR5 promoter. AIDS Res Hum Retroviruses. 1998 Nov 20;14(17):1509–1519. doi: 10.1089/aid.1998.14.1509. [DOI] [PubMed] [Google Scholar]
  26. Los M., Schenk H., Hexel K., Baeuerle P. A., Dröge W., Schulze-Osthoff K. IL-2 gene expression and NF-kappa B activation through CD28 requires reactive oxygen production by 5-lipoxygenase. EMBO J. 1995 Aug 1;14(15):3731–3740. doi: 10.1002/j.1460-2075.1995.tb00043.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Manna S. K., Zhang H. J., Yan T., Oberley L. W., Aggarwal B. B. Overexpression of manganese superoxide dismutase suppresses tumor necrosis factor-induced apoptosis and activation of nuclear transcription factor-kappaB and activated protein-1. J Biol Chem. 1998 May 22;273(21):13245–13254. doi: 10.1074/jbc.273.21.13245. [DOI] [PubMed] [Google Scholar]
  28. Meister A., Anderson M. E. Glutathione. Annu Rev Biochem. 1983;52:711–760. doi: 10.1146/annurev.bi.52.070183.003431. [DOI] [PubMed] [Google Scholar]
  29. Mercurio F., Manning A. M. NF-kappaB as a primary regulator of the stress response. Oncogene. 1999 Nov 1;18(45):6163–6171. doi: 10.1038/sj.onc.1203174. [DOI] [PubMed] [Google Scholar]
  30. Meyer M., Pahl H. L., Baeuerle P. A. Regulation of the transcription factors NF-kappa B and AP-1 by redox changes. Chem Biol Interact. 1994 Jun;91(2-3):91–100. doi: 10.1016/0009-2797(94)90029-9. [DOI] [PubMed] [Google Scholar]
  31. Meyer M., Schreck R., Baeuerle P. A. H2O2 and antioxidants have opposite effects on activation of NF-kappa B and AP-1 in intact cells: AP-1 as secondary antioxidant-responsive factor. EMBO J. 1993 May;12(5):2005–2015. doi: 10.1002/j.1460-2075.1993.tb05850.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Panzer U., Schneider A., Wilken J., Thompson D. A., Kent S. B., Stahl R. A. The chemokine receptor antagonist AOP-RANTES reduces monocyte infiltration in experimental glomerulonephritis. Kidney Int. 1999 Dec;56(6):2107–2115. doi: 10.1046/j.1523-1755.1999.00767.x. [DOI] [PubMed] [Google Scholar]
  33. Pathania V., Syal N., Pathak C. M., Khanduja K. L. Vitamin E suppresses the induction of reactive oxygen species release by lipopolysaccharide, interleukin-1beta and tumor necrosis factor-alpha in rat alveolar macrophages. J Nutr Sci Vitaminol (Tokyo) 1999 Dec;45(6):675–686. doi: 10.3177/jnsv.45.675. [DOI] [PubMed] [Google Scholar]
  34. Raport C. J., Gosling J., Schweickart V. L., Gray P. W., Charo I. F. Molecular cloning and functional characterization of a novel human CC chemokine receptor (CCR5) for RANTES, MIP-1beta, and MIP-1alpha. J Biol Chem. 1996 Jul 19;271(29):17161–17166. doi: 10.1074/jbc.271.29.17161. [DOI] [PubMed] [Google Scholar]
  35. Raport C. J., Schweickart V. L., Chantry D., Eddy R. L., Jr, Shows T. B., Godiska R., Gray P. W. New members of the chemokine receptor gene family. J Leukoc Biol. 1996 Jan;59(1):18–23. doi: 10.1002/jlb.59.1.18. [DOI] [PubMed] [Google Scholar]
  36. Roebuck K. A. Oxidant stress regulation of IL-8 and ICAM-1 gene expression: differential activation and binding of the transcription factors AP-1 and NF-kappaB (Review). Int J Mol Med. 1999 Sep;4(3):223–230. doi: 10.3892/ijmm.4.3.223. [DOI] [PubMed] [Google Scholar]
  37. Saccani A., Saccani S., Orlando S., Sironi M., Bernasconi S., Ghezzi P., Mantovani A., Sica A. Redox regulation of chemokine receptor expression. Proc Natl Acad Sci U S A. 2000 Mar 14;97(6):2761–2766. doi: 10.1073/pnas.97.6.2761. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Sahnoun Z., Jamoussi K., Zeghal K. M. Radicaux libres et anti-oxydants: physiologie, pathologie humaine et aspects thérapeutiques (ilème partie). Therapie. 1998 Jul-Aug;53(4):315–339. [PubMed] [Google Scholar]
  39. Samson M., Labbe O., Mollereau C., Vassart G., Parmentier M. Molecular cloning and functional expression of a new human CC-chemokine receptor gene. Biochemistry. 1996 Mar 19;35(11):3362–3367. doi: 10.1021/bi952950g. [DOI] [PubMed] [Google Scholar]
  40. Satriano J. A., Shuldiner M., Hora K., Xing Y., Shan Z., Schlondorff D. Oxygen radicals as second messengers for expression of the monocyte chemoattractant protein, JE/MCP-1, and the monocyte colony-stimulating factor, CSF-1, in response to tumor necrosis factor-alpha and immunoglobulin G. Evidence for involvement of reduced nicotinamide adenine dinucleotide phosphate (NADPH)-dependent oxidase. J Clin Invest. 1993 Sep;92(3):1564–1571. doi: 10.1172/JCI116737. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Sbarra A. J., Paul B. B., Jacobs A. A., Strauss R. R., Mitchell G. W., Jr Biochemical aspects of phagocytic cells as related to bactericidal function. J Reticuloendothel Soc. 1972 May;11(5):492–502. [PubMed] [Google Scholar]
  42. Schreck R., Albermann K., Baeuerle P. A. Nuclear factor kappa B: an oxidative stress-responsive transcription factor of eukaryotic cells (a review). Free Radic Res Commun. 1992;17(4):221–237. doi: 10.3109/10715769209079515. [DOI] [PubMed] [Google Scholar]
  43. Schreck R., Rieber P., Baeuerle P. A. Reactive oxygen intermediates as apparently widely used messengers in the activation of the NF-kappa B transcription factor and HIV-1. EMBO J. 1991 Aug;10(8):2247–2258. doi: 10.1002/j.1460-2075.1991.tb07761.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Schulze-Osthoff K., Los M., Baeuerle P. A. Redox signalling by transcription factors NF-kappa B and AP-1 in lymphocytes. Biochem Pharmacol. 1995 Sep 7;50(6):735–741. doi: 10.1016/0006-2952(95)02011-z. [DOI] [PubMed] [Google Scholar]
  45. Shi M. M., Godleski J. J., Paulauskis J. D. Regulation of macrophage inflammatory protein-1alpha mRNA by oxidative stress. J Biol Chem. 1996 Mar 8;271(10):5878–5883. doi: 10.1074/jbc.271.10.5878. [DOI] [PubMed] [Google Scholar]
  46. Siebenlist U., Franzoso G., Brown K. Structure, regulation and function of NF-kappa B. Annu Rev Cell Biol. 1994;10:405–455. doi: 10.1146/annurev.cb.10.110194.002201. [DOI] [PubMed] [Google Scholar]
  47. Thivierge M., Le Gouill C., Tremblay M. J., Stanková J., Rola-Pleszczynski M. Prostaglandin E2 induces resistance to human immunodeficiency virus-1 infection in monocyte-derived macrophages: downregulation of CCR5 expression by cyclic adenosine monophosphate. Blood. 1998 Jul 1;92(1):40–45. [PubMed] [Google Scholar]
  48. Topham P. S., Csizmadia V., Soler D., Hines D., Gerard C. J., Salant D. J., Hancock W. W. Lack of chemokine receptor CCR1 enhances Th1 responses and glomerular injury during nephrotoxic nephritis. J Clin Invest. 1999 Dec;104(11):1549–1557. doi: 10.1172/JCI7707. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Traenckner E. B., Wilk S., Baeuerle P. A. A proteasome inhibitor prevents activation of NF-kappa B and stabilizes a newly phosphorylated form of I kappa B-alpha that is still bound to NF-kappa B. EMBO J. 1994 Nov 15;13(22):5433–5441. doi: 10.1002/j.1460-2075.1994.tb06878.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Vachier I., Damon M., Le Doucen C., de Paulet A. C., Chanez P., Michel F. B., Godard P. Increased oxygen species generation in blood monocytes of asthmatic patients. Am Rev Respir Dis. 1992 Nov;146(5 Pt 1):1161–1166. doi: 10.1164/ajrccm/146.5_Pt_1.1161. [DOI] [PubMed] [Google Scholar]
  51. Verhasselt V., Goldman M., Willems F. Oxidative stress up-regulates IL-8 and TNF-alpha synthesis by human dendritic cells. Eur J Immunol. 1998 Nov;28(11):3886–3890. doi: 10.1002/(SICI)1521-4141(199811)28:11<3886::AID-IMMU3886>3.0.CO;2-M. [DOI] [PubMed] [Google Scholar]
  52. Wada T., Furuichi K., Segawa-Takaeda C., Shimizu M., Sakai N., Takeda S. I., Takasawa K., Kida H., Kobayashi K. I., Mukaida N. MIP-1alpha and MCP-1 contribute to crescents and interstitial lesions in human crescentic glomerulonephritis. Kidney Int. 1999 Sep;56(3):995–1003. doi: 10.1046/j.1523-1755.1999.00646.x. [DOI] [PubMed] [Google Scholar]
  53. Xing Z., Jordana M., Braciak T., Ohtoshi T., Gauldie J. Lipopolysaccharide induces expression of granulocyte/macrophage colony-stimulating factor, interleukin-8, and interleukin-6 in human nasal, but not lung, fibroblasts: evidence for heterogeneity within the respiratory tract. Am J Respir Cell Mol Biol. 1993 Sep;9(3):255–263. doi: 10.1165/ajrcmb/9.3.255. [DOI] [PubMed] [Google Scholar]

Articles from Mediators of Inflammation are provided here courtesy of Wiley

RESOURCES