Experimental and Molecular Medicine

Korean Society for Biochemistry and Molecular Biongy (생화학분자생물학회)
권호 표지

$\beta$-Carotene inhibits inflammatory gene expression in lipopolysaccharide-stimulated macrophages by suppressing redox-based NF-$\kappa$B activation

Bai, Se-Kyung;Lee, Seon-Jin;Na, Hee-Jun;Ha, Kwon-Soo;Han, Jeong-A;Lee, Han-Soo;Kwon, Young-Guen;Chung, Cha-Kwon;Kim, Young-Myeong

  • Published : 2005.08.31
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Abstract

-Carotene has shown antioxidant and anti- inflammatory activities; however, its molecular mechanism has not been clearly defined. We examined in vitro and in vivo regulatory function of -carotene on the production of nitric oxide (NO) and PGE2 as well as expression of inducible NO synthase (iNOS), cyclooxygenase-2, TNF-, and IL-1. - Carotene inhibited the expression and production of these inflammatory mediators in both LPS- stimulated RAW264.7 cells and primary macrophages in a dose-dependent fashion as well as in LPS-administrated mice. Furthermore, this compound suppressed NF-B activation and iNOS promoter activity in RAW264.7 cells stimulated with LPS. -Carotene blocked nuclear translocation of NF-B p65 subunit, which correlated with its inhibitory effect on IB phosphorylation and degradation. This compound directly blocked the intracellular accumulation of reactive oxygen species in RAW264.7 cells stimulated with LPS as both the NADPH oxidase inhibitor diphenylene iodonium and antioxidant pyrrolidine dithiocarbamate did. The inhibition of NADPH oxidase also inhibited NO production, iNOS expression, and iNOS promoter activity. These results suggest that - carotene possesses anti-inflammatory activity by functioning as a potential inhibitor for redox-based NF-B activation, probably due to its antioxidant activity.

Keywords

References

  1. Barnes PJ, Karin M. Nuclear factor-$\kappa$B: a pivotal transcription factor in chronic inflammatory diseases. N Engl J Med 1997;336:1066-71 https://doi.org/10.1056/NEJM199704103361506
  2. Black RA, Rauch CT, Kozlosky CJ, Peschon JJ, Slack JL, Wolfson MF, Castner BJ, Stocking KL, Reddy P, Srinivasan S, Nelson N, Boiani N, Schooley KA, Gerhart M, Davis R, Fitzner JN, Johnson RS, Paxton RJ, March CJ, Cerretti DP. A metalloproteinase disintegrin that releases tumournecrosis $factor-{\alpha}$ from cells. Nature 1997;385:729-33 https://doi.org/10.1038/385729a0
  3. Bokoch GM, Knaus UG. NADPH oxidases: not just for leukocytes anymore! Trends Biochem Sci 2003;28:502-8 https://doi.org/10.1016/S0968-0004(03)00194-4
  4. Butcher BA, Kim L, Johnson PF, Denkers EY. Toxoplasma gondii tachyzoites inhibit proinflammatory cytokine induction in infected macrophages by preventing nuclear translocation of the transcription factor $NF-{\kappa}B$. J Immunol 2001;167: 2193-201
  5. Chiao PJ, Na R, Niu J, Sclabas GM, Dong Q, Curley SA. Role of Rel/NF-$\kappa$B transcription factors in apoptosis of human hepatocellular carcinoma cells. Cancer 2002;95: 1696-705 https://doi.org/10.1002/cncr.10829
  6. Curran FJ, Sattar N, Talwar D, Baxter JN, Imrie CW. Relationship of carotenoid and vitamins A and E with the acute inflammatory response in acute pancreatitis. Br J Surg 2000;87:301-5 https://doi.org/10.1046/j.1365-2168.2000.01375.x
  7. de Martin R, Vanhove B, Cheng Q, Hofer E, Csizmadia V, Winkler H, Bach FH. Cytokine-inducible expression in endothelial cells of an $I{\kappa}B{\alpha}$-like gene is regulated by $NF{\kappa}B$. EMBO J 1993;12:2773-9
  8. Dichtl W, Nilsson L, Goncalves I, Ares MP, Banfi C, Calara F, Hamsten A, Eriksson P, Nilsson J. Very low-density lipoprotein activates nuclear $factor-{\kappa}B$ in endothelial cells. Circ Res 1999;84:1085-94
  9. Everett SA, Dennis MF, Patel KB, Maddix S, Kundu SC, Willson RL. Scavenging of nitrogen dioxide, thiyl, and sulfonyl free radicals by the nutritional antioxidant ${\beta}-Carotene$. J Biol Chem 1996;271:3988-94 https://doi.org/10.1074/jbc.271.8.3988
  10. Flohe L, Brigelius-Flohe R, Saliou C, Traber MG, Packer L. Redox regulation of $NF-{\kappa}B$ activation. Free Radic Biol Med 1997; 22:1115-26 https://doi.org/10.1016/S0891-5849(96)00501-1
  11. Gilroy DW, Lawrence T, Perretti M, Rossi AG. Inflammatory resolution: new opportunities for drug discovery. Nat Rev Drug Discov 2004;3:401-16 https://doi.org/10.1038/nrd1383
  12. Guslandi M. Nitric oxide and inflammatory bowel diseases. Eur J Clin Invest 1998;28:904-7 https://doi.org/10.1046/j.1365-2362.1998.00377.x
  13. Guzik TJ, Korbut R, Adamek-Guzik T. Nitric oxide and superoxide in inflammation and immune regulation. J Physiol Pharmacol 2003;54:469-87
  14. Han YJ, Kwon YG, Chung HT, Lee SK, Simmons RL, Billiar TR, Kim YM. Antioxidant enzymes suppress nitric oxide production through the inhibition of $NF-{\kappa}B$ activation: role of $H__2O_2$ and nitric oxide in inducible nitric oxide synthase expression in macrophages. Nitric Oxide2001; 5:504-13 https://doi.org/10.1006/niox.2001.0367
  15. Heiss E, Herhaus C, Klimo K, Bartsch H, Gerhauser C. Nuclear factor ${\kappa}B$ is a molecular target for sulforaphanemediated anti-inflammatory mechanisms. J Biol Chem 2001; 276: 32008-15 https://doi.org/10.1074/jbc.M104794200
  16. Heliovaara M, Knekt P, Aho K, Aaran RK, Alfthan G., Aromaa A. Serum antioxidants and risk of rheumatoid arthritis. Ann Rheum Dis 1994;53:51-3 https://doi.org/10.1136/ard.53.1.51
  17. Kabe Y, Ando K, Hirao S, Yoshida M, Handa H. Redox regulation of $NF-{\kappa}B$ activation: distinct redox regulation between the cytoplasm and the nucleus. Antioxid Redox Signal 2005;7: 395-403 https://doi.org/10.1089/ars.2005.7.395
  18. Kaltschmidt B, Uherek M, Wellmann H, Volk B, Kaltschmidt C. Inhibition of $NF-{\kappa}B$ potentiates amyloid beta-mediated neuronal apoptosis. Proc Natl Acad Sci USA 1999;96: 9409-14 https://doi.org/10.1073/pnas.96.16.9409
  19. Kim KM, Chun SB, Koo MS, Choi WJ, Kim TW, Kwon YG, Chung HT, Billiar TR, Kim YM. Differential regulation of NO availability from macrophages and endothelial cells by the garlic component S-allyl cysteine. Free Radic Biol Med 2001;30:747-56 https://doi.org/10.1016/S0891-5849(01)00460-9
  20. Kim YM, Talanian RV, Billiar TR. Nitric oxide inhibits apoptosis by preventing increases in caspase-3-like activity via two distinct mechanisms. J Biol Chem 1997;272:31138-48 https://doi.org/10.1074/jbc.272.49.31138
  21. Leach M, Hamilton LC, Olbrich A, Wray GM, Thiemermann C. Effects of inhibitors of the activity of cyclo-oxygenase-2 on the hypotension and multiple organ dysfunction caused by endotoxin: a comparison with dexamethasone. Br J Pharmacol 1998;124:586-92 https://doi.org/10.1038/sj.bjp.0701869
  22. Lee SJ, Bai SK, Lee KS, Namkoong S, Na HJ, Ha KS, Han JA, Yim SV, Chang K, Kwon YG, Lee SK, Kim YM. Astaxanthin inhibits nitric oxide production and inflammatory gene expression by suppressing $I{\kappa}B$ kinase-dependent $NF-{\kappa}B$ activation. Mol Cells 2003a;16:97-105
  23. Lee ZW, Kwon SM, Kim SW, Yi SJ, Kim YM, Ha KS. Activation of in situ tissue transglutaminase by intracellular reactive oxygen species. Biochem Biophys Res Commun 2003b;305:633-40 https://doi.org/10.1016/S0006-291X(03)00835-0
  24. Makarov SS. $NF-{\kappa}B$ as a therapeutic target in chronic inflammation: recent advances. Mol Med Today 2000;6: 441-8 https://doi.org/10.1016/S1357-4310(00)01814-1
  25. Meyer M, Caselmann WH, Schluter V, Schreck R, Hofschneider PH, Baeuerle PA. Hepatitis B virus transactivator MHBst: activation of $NF-{\kappa}B$, selective inhibition by antioxidants and integral membrane localization. EMBO J 1992;11:2991-3001
  26. Napoli C, Ignarro LJ. Nitric oxide and atherosclerosis. Nitric Oxide 2001;5:88-97 https://doi.org/10.1006/niox.2001.0337
  27. Neuzil J, Weber C, Kontush A. The role of vitamin E in atherogenesis: linking the chemical, biological and clinical aspects of the disease. Atherosclerosis 2001;157:257-83 https://doi.org/10.1016/S0021-9150(00)00741-3
  28. Palozza P, Serini S, Torsello A, Di Nicuolo F, Piccioni E, Ubaldi V, Pioli C, Wolf FI, Calviello G. ${\beta}-carotene$ regulates NF-kappaB DNA-binding activity by a redox mechanism in human leukemia and colon adenocarcinoma cells. J Nutr 2003;133:381-8
  29. Pierce GF. Macrophages: important physiologic and pathologic sources of polypeptide growth factors. Am J Respir Cell Mol Biol 1990;2:233-4
  30. Rhodus NL, Cheng B, Myers S, Bowles W, Ho V, Ondrey F. A comparison of the pro-inflammatory, $NF-{\kappa}B-dependent$ cytokines: $TNF-{\alpha}$, $IL-1{\alpha}$, IL-6, and IL-8 in different oral fluids from oral lichen planus patients. Clin Immunol 2005;114: 278-83 https://doi.org/10.1016/j.clim.2004.12.003
  31. Ritchlin CT, Haas-Smith SA, Li P, Hicks DG., Schwarz EM. Mechanisms of TNF-$\alpha$- and RANKL-mediated osteoclastogenesis and bone resorption in psoriatic arthritis. J Clin Invest 2003;111:821-31
  32. Schreck R, Meier B, Mannel DN, Droge W, Baeuerle PA. Dithiocarbamates as potent inhibitors of nuclear factor ${\kappa}B$ activation in intact cells. J Exp Med 1992;175:1181-94 https://doi.org/10.1084/jem.175.5.1181
  33. Simons RK, Junger WG, Loomis WH, Hoyt DB. Acute lung injury in endotoxemic rats is associated with sustained circulating IL-6 levels and intrapulmonary CINC activity and neutrophil recruitment--role of circulating $TNF-{\alpha}$ and $IL-{\beta}$? Shock 1996;6:39-45
  34. Smith TA. Carotenoids and cancer: prevention and potential therapy. Br J Biomed Sci 1998;55:268-75
  35. Storz P, Toker A. Protein kinase D mediates a stress-induced $NF-{\kappa}B$ activation and survival pathway. EMBO J 2003; 22:109-20 https://doi.org/10.1093/emboj/cdg009
  36. Szabo C, Southan GJ, Thiemermann C. Beneficial effects and improved survival in rodent models of septic shock with S-methylisothiourea sulfate, a potent and selective inhibitor of inducible nitric oxide synthase. Proc Natl Acad Sci USA 1994;91:12472-6 https://doi.org/10.1073/pnas.91.26.12472
  37. Tak PP, Gerlag DM, Aupperle KR, van de Geest DA, Overbeek M, Bennett BL, Boyle DL, Manning AM, Firestein GS. Inhibitor of nuclear factor ${\kappa}B$ kinase beta is a key regulator of synovial inflammation. Arthritis Rheum 2001; 44:1897-907 https://doi.org/10.1002/1529-0131(200108)44:8<1897::AID-ART328>3.0.CO;2-4
  38. Thornberry NA, Bull HG, Calaycay JR, Chapman KT, Howard AD, Kostura MJ, Miller DK, Molineaux SM, Weidner JR, Aunins J. A novel heterodimeric cysteine protease is required for $interleukin-1{\beta}$ processing in monocytes. Nature 1992;356: 768-74 https://doi.org/10.1038/356768a0
  39. Traenckner EB, Pahl HL, Henkel T, Schmidt KN, Wilk S, Baeuerle PA. Phosphorylation of human $I{\kappa}B-{\alpha}$ on serines 32 and 36 controls $I{\kappa}B-{\alpha}$ proteolysis and $NF-{\kappa}B$ activation in response to diverse stimuli. EMBO J 1995;14:2876-83
  40. van der Saag PT, Caldenhoven E, van de Stolpe A. Molecular mechanisms of steroid action: a novel type of cross-talk between glucocorticoids and $NF-{\kappa}B$ transcription factors. Eur Respir J Suppl 1996;22:146s-53s
  41. Vivekananthan DP, Penn MS, Sapp SK, Hsu A, Topol EJ. Use of antioxidant vitamins for the prevention of cardiovascular disease: meta-analysis of randomised trials. Lancet 2003;361:2017-23 https://doi.org/10.1016/S0140-6736(03)13637-9
  42. Witschi H. Carcinogenic activity of cigarette smoke gas phase and its modulation by ${\beta}-carotene$ and N-acetylcysteine. Toxicol Sci 2005;84:81-7 https://doi.org/10.1093/toxsci/kfi043
  43. Xie QW, Kashiwabara Y, Nathan C. Role of transcription factor $NF-{\kappa}B/Re$l in induction of nitric oxide synthase. J Biol Chem 1994;269:4705-8