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Nitric Oxide Synthesis is Modulated by 1,25-Dihydroxyvitamin D3 and Interferon-${\gamma}$ in Human Macrophages after Mycobacterial Infection

  • Lee, Ji-Sook (Department of Microbiology, College of Medicine, Chungnam National University) ;
  • Yang, Chul-Su (Department of Microbiology, College of Medicine, Chungnam National University) ;
  • Shin, Dong-Min (Department of Microbiology, College of Medicine, Chungnam National University) ;
  • Yuk, Jae-Min (Department of Microbiology, College of Medicine, Chungnam National University) ;
  • Son, Ji-Woong (Department of Internal Medicine, College of Medicine, Konyang University) ;
  • Jo, Eun-Kyeong (Department of Microbiology, College of Medicine, Chungnam National University)
  • Received : 2009.09.04
  • Accepted : 2009.09.19
  • Published : 2009.10.31

Abstract

Background: Little information is available the role of Nitric Oxide (NO) in host defenses during human tuberculosis (TB) infection. We investigated the modulating factor(s) affecting NO synthase (iNOS) induction in human macrophages. Methods: Both iNOS mRNA and protein that regulate the growth of mycobacteria were determined using reverase transcriptase-polymerase chain reaction and western blot analysis. The upstream signaling pathways were further investigated using iNOS specific inhibitors. Results: Here we show that combined treatment with 1,25-dihydroxyvitamin D3 (1,25-D3) and Interferon (IFN)-${\gamma}$ synergistically enhanced NO synthesis and iNOS expression induced by Mycobacterium tuberculosis (MTB) or by its purified protein derivatives in human monocyte-derived macrophages. Both the nuclear factor-${\kappa}B$ and MEK1-ERK1/2 pathways were indispensable in the induction of iNOS expression, as shown in toll like receptor 2 stimulation. Further, the combined treatment with 1,25-D3 and IFN-${\gamma}$ was more potent than either agent alone in the inhibition of intracellular MTB growth. Notably, this enhanced effect was not explained by increased expression of cathelicidin, a known antimycobacterial effector of 1,25-D3. Conclusion: These data support a key role of NO in host defenses against TB and identify novel modulating factors for iNOS induction in human macrophages.

Keywords

References

  1. Tomioka H: Prospects for development of new anti-mycobacterial drugs. J Infect Chemother 6;8-20, 2000 https://doi.org/10.1007/s101560050043
  2. Chan J, Xing Y, Magliozzo RS, Bloom BR: Killing of virulent Mycobacterium tuberculosis by reactive nitrogen intermediates produced by activated murine macrophages. J Exp Med 175;1111-1122, 1992 https://doi.org/10.1084/jem.175.4.1111
  3. Flynn JL, Scanga CA, Tanaka KE, Chan J: Effects of amino-guanidine on latent murine tuberculosis. J Immunol 160; 1796-1803, 1998
  4. Lon R, Light B, Talbot JA: Mycobacteriocidal action of exogenous nitric oxide. Antimicrob Agents Chemother 43;403-405, 1999 https://doi.org/10.1093/jac/43.3.403
  5. Yu K, Mitchell C, Xing Y, Magliozzo RS, Bloom BR, Chan J: Toxicity of nitrogen oxides and related oxidants on mycobacteria: M. tuberculosis is resistant to peroxynitrite anion. Tuber Lung Dis 79;191-198, 1999 https://doi.org/10.1054/tuld.1998.0203
  6. Nicholson S, Bonecini-Almeida Mad G, Lapa e Silva JR, Nathan C, Xie QW, Mumford R, Weidner JR, Calaycay J, Geng J, Boechat N, Linhares C, Rom W, Ho JR: Inducible nitric oxide synthase in pulmonary alveolar macrophages from patients with tuberculosis. J Exp Med 183;2293-2302, 1996 https://doi.org/10.1084/jem.183.5.2293
  7. Wang CH, Liu CY, Lin HC, Yu CT, Chung KF, Kuo HP: Increased exhaled nitric oxide in active pulmonary tuberculosis due to inducible NO synthase upregulation in alveolar macrophages. Eur Respir J 11;809-815, 1998 https://doi.org/10.1183/09031936.98.11040809
  8. Rich EA, Torres M, Sada E, Finegan CK, Hamilton BD, Toossi Z: Mycobacterium tuberculosis (MTB)-stimulated production of nitric oxide by human alveolar macrophages and relationship of nitric oxide production to growth inhibition of MTB. Tuberc Lung Dis 78;247-255, 1997 https://doi.org/10.1016/S0962-8479(97)90005-8
  9. Rockett KA, Brookes R, Udalova I, Vidal V, Hill AV, Kwiatkowski D: 1,25-Dihydroxyvitamin D3 induces nitric oxide synthase and suppresses growth of Mycobacterium tuberculosis in a human macrophage-like cell line. Infect Immun 66;5314-5321, 1998
  10. Liu PT, Stenger S, Li H, Wenzel L, Tan BH, Krutzik SR, Ochoa MT, Schauber J, Wu K, Meinken C, Kamen DL, Wagner M, Bals R, Steinmeyer A, Zugel U, Gallo RL, Eisenberg D, Hewison M, Hollis BW, Adams JS, Bloom BR, Modlin RL: Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response. Science 311;1770-1773, 2006 https://doi.org/10.1126/science.1123933
  11. Nathan C: Role of iNOS in human host defense. Science 312;1874-1875, 2006
  12. Yang CS, Lee JS, Song CH, Hur GM, Lee SJ, Tanaka S, Akira S, Paik TH, Jo EK: Protein kinase C zeta plays an essential role for Mycobacterium tuberculosis -induced extracellular signal-regulated kinase 1/2 activation in monocytes/macrophages via Toll-like receptor 2. Cell Microbiol 9;382-389, 2007 https://doi.org/10.1111/j.1462-5822.2006.00797.x
  13. Madrigal JL, Russo CD, Gavrilyuk V, Feinstein DL: Effects of noradrenaline on neuronal NOS2 expression and viability. Antioxid Redox Signal 8;885-892, 2006 https://doi.org/10.1089/ars.2006.8.885
  14. Ding AH, Nathan CF, Stuehr DJ: Release of reactive nitrogen intermediates and reactive oxygen intermediates from mouse peritoneal macrophages. Comparison of activating cytokines and evidence for independent production. J Immunol 141;2407-2412, 1998
  15. Yang CS, Shin DM, Kim KH, Lee ZW, Lee CH, Park SG, Bae YS, Jo EK: NADPH oxidase 2 interaction with TLR2 is required for efficient innate immune responses to mycobacteria via cathelicidin expression. J mmunol 182:3696-3705, 2009 https://doi.org/10.4049/jimmunol.0802217
  16. MacMicking J, Xie QW, Nathan C: Nitric oxide and macrophage function. Annu Rev Immunol 15;323-350, 1997 https://doi.org/10.1146/annurev.immunol.15.1.323
  17. Schneemann M, Schoedon G, Hofer S, Blau N, Guerrero L, Schaffner A: Nitric oxide synthase is not a constituent of the antimicrobial armature of human mononuclear phagocytes. J Infect Dis 167;1358-1363, 1993 https://doi.org/10.1093/infdis/167.6.1358
  18. Ghosh S, May MJ, Kopp EB: NF-kappa B and Rel proteins: evolutionarily conserved mediators of immune responses. Annu Rev Immunol 16;225-260, 1998 https://doi.org/10.1146/annurev.immunol.16.1.225
  19. Jaramillo M, Gowda DC, Radzioch D, Olivier M: Hemozoin increases IFN-gamma-inducible macrophage nitric oxide generation through extracellular signal-regulated kinase-and NF-kappa B-dependent pathways. J Immunol 171; 4243-4253, 2003 https://doi.org/10.4049/jimmunol.171.8.4243
  20. Natarajan K, Singh S, Burke TR Jr, Grunberger D, Aggarwal BB: Caffeic acid phenethyl ester is a potent and specific inhibitor of activation of nuclear transcription factor NF-kappaB. Proc Natl Acad Sci USA 93;9090-9095, 1996 https://doi.org/10.1073/pnas.93.17.9090
  21. Sugawara I, Yamada H, Li C, Mizuno S, Takeuchi O, Akira S: Mycobacterial infection in TLR2 and TLR6 knockout mice. Microbiol Immunol 47;327-336, 2003 https://doi.org/10.1111/j.1348-0421.2003.tb03404.x
  22. Chan ED, Winston BW, Uh ST, Wynes MW, Rose DM, Riches DW: Evaluation of the role of mitogen-activated protein kinases in the expression of inducible nitric oxide synthase by IFN-$\gamma$ and TNF-$\alpha$ in mouse macrophages. J Immunol 162;415-422, 1999
  23. Denis M: Tumor necrosis factor and granulocyte macrophage colony stimulating factor stimulate human macrophage to restrict growth of virulent Mycobacterium avium and to kill avirulent M. avium: killing effector mechanism depends on the generation of reactive nitrogen intermediates. J Leukoc Biol 9;380-387, 1991
  24. Weinberg JB, Misukonis MA, Shami PJ, Mason SN, Sauls DL, Dittman WA, Wood ER, Smith GK, McDonald B, Bachus KE, Haney AF, Granger DL: Human mononuclear phagocytes inducible nitric oxide synthase (NOS): analysis if iNOS mRNA, iNOS protein, bioprotein and nitric oxide production by blood monocytes and peritoneal macrophages. Blood 86;1184-1195, 1995
  25. Padgett EL, Pruett SB: Evaluation of nitrite production by human monocyte derived macrophages. Biochem Biophys Res Commun 186;775-781, 1992 https://doi.org/10.1016/0006-291X(92)90813-Z
  26. Sable SB, Goyal D, Verma I, Behera D, Khuller GK: Lung and blood mononuclear cell responses of TB patients to mycobacterial proteins. Eur Respir J 29;337-346, 2007
  27. Thoma-Uszynski S, Stenger S, Takeuchi O, Ochoa MT, Engele M, Sieling PA, Barnes PF, Rollinghoff M, Bolcskei PL, Wagner M, Akira S, Norgard MV, Belisle JT, Godowski PJ, Bloom BR, Modlin RL: Induction of direct antimicrobial activity through mammalian toll-like receptors. Science 291;1544-1547, 2001 https://doi.org/10.1126/science.291.5508.1544
  28. Nozaki Y, Hasegawa Y, Ichiyama S, Nakashima I, Shimokata K: Mechanism of nitric oxide-dependent killing of Mycobacterium bovis BCG in human alveolar macrophages. Infect Immun 65;3644-3647, 1997
  29. Bose M, Farnia P, Sharma S, Chattopadhya D, Saha K: Nitric oxide dependent killing of Mycobacterium tuberculosis by human mononuclear phagocytes from patients with active tuberculosis. Int J Immunopathol Pharmacol 12;69-79, 1999
  30. Jaramillo M, Naccache PH, Olivier M: Monosodium urate crystals synergize with IFN-gamma to generate macrophage nitric oxide: involvement of extracellular signal-regulated kinase 1/2 and NF-kappa B. J Immunol 172;5734-5742, 2004 https://doi.org/10.4049/jimmunol.172.9.5734
  31. Blanchette J, Jaramillo M, Olivier M: Signalling events involved in interferon-gamma-inducible macrophage nitric oxide generation. Immunology 108;513-522, 2003 https://doi.org/10.1046/j.1365-2567.2003.01620.x
  32. Haddad JJ: Antioxidant and prooxidant mechanisms in the regulation of redox(y)-sensitive transcription factors. Cell Signal 14;879-897, 2002 https://doi.org/10.1016/S0898-6568(02)00053-0
  33. Manolagas SC, Hustmyer FG, Yu XP: Immunomodulating properties of 1,25-dihydroxyvitamin D3. Kidney Int Suppl 29;S9-16, 1990
  34. Remer KA, Brcic M, Sauter KS, Jungi TW: Human mono-cytoid cells as a model to study Toll-like receptor-mediated activation. J Immunol Methods 313;1-10, 2006 https://doi.org/10.1016/j.jim.2005.07.026
  35. Davies PD: A possible link between vitamin D deficiency and impaired host defence to Mycobacterium tuberculosis. Tubercle 66;301-306, 1985 https://doi.org/10.1016/0041-3879(85)90068-6
  36. Roy S, Frosham A, Saha B, Hazra SK, Mascie-Taylor CG, Hill AV: Association of vitamin D receptor genotype with leprosy type. J Infect Dis 179;187-191, 1999 https://doi.org/10.1086/314536
  37. Wilkinson RJ, Llewelyn M, Toossi Z, Patel P, Pasvol G, Lalvani A, Wright D, Latif M, Davidson RN: Influence of vitamin D deficiency and vitamin D receptor polymorphisms on tuberculosis among Gujarati Asians in west London: a case-control study. Lancet 355;618-621, 2000 https://doi.org/10.1016/S0140-6736(99)02301-6
  38. Crowle AJ, Ross EJ, May MH: Inhibition by 1,25(OH)2-vitamin D3 of the multiplication of virulent tubercle bacilli in cultured human macrophages. Infect Immun 55;2945-2950, 1987
  39. Rook GA, Steele J, Fraher L, Barker S, Karmali R, O'Riordan J, Stanford J: Vitamin D3, gamma interferon, and control of proliferation of Mycobacterium tuberculosis by human monocytes. Immunology 57;159-163, 1986
  40. Adams JS, Modlin RL, Diz MM, Barnes PF: Potentiation of the macrophage 25-hydroxyvitamin D-1-hydroxylation reaction by human tuberculous pleural effusion fluid. J Clin Endocrinol Metab 69;457-460, 1989 https://doi.org/10.1210/jcem-69-2-457
  41. Dusso AS, Kamimura S, Gallieni M, Zhong M, Negrea L, Shapiro S, Slatopolsky E: Gamma-Interferon-induced resistance to 1,25-(OH)2 D3 in human monocytes and macrophages: a mechanism for the hypercalcemia of various granulomatoses. J Clin Endocrinol Metab 82;2222-2232, 1997 https://doi.org/10.1210/jc.82.7.2222
  42. Kikuchi H, Iizuka R, Sugiyama S, Gon G, Mori H, Arai M, Mizumoto K, Imajoh-Ohmi S: Monocytic differentiation modulates apoptotic response to cytotoxic anti-Fas antibody and tumor necrosis factor alpha in human monoblast U937 cells. J Leukoc Biol 60;778-783, 1996 https://doi.org/10.1002/jlb.60.6.778
  43. Jourd'heuil D, Mills L, Miles AM, Grisham MB: Effect of nitric oxide on hemoprotein-catalyzed oxidative reactions. Nitric Oxide 2;37-44, 1998 https://doi.org/10.1006/niox.1998.0167

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