The Korean Journal of Physiology and Pharmacology

The Korean Society of Pharmacology (대한약리학회)
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Inhibition of Inducible Nitric Oxide Synthase Expression by YS 49, a Synthetic Isoquinoline Alkaloid, in ROS 17/2.8 Cells Activated with $TNF-{\alpha},\;IFN-{\gamma}$ and LPS

  • Kang, Young-Jin (Department of Pharmacology, College of Medicine, Institute of Health Sciences, Gyeongsang National University) ;
  • Kang, Sun-Young (Department of Pharmacology, College of Medicine, Institute of Health Sciences, Gyeongsang National University) ;
  • Lee, Young-Soo (Department of Pharmacology, College of Medicine, Institute of Health Sciences, Gyeongsang National University) ;
  • Park, Min-Kyu (Department of Pharmacology, College of Medicine, Institute of Health Sciences, Gyeongsang National University) ;
  • Kim, Hye-Jung (Department of Pharmacology, College of Medicine, Institute of Health Sciences, Gyeongsang National University) ;
  • Seo, Han-Geuk (Department of Pharmacology, College of Medicine, Institute of Health Sciences, Gyeongsang National University) ;
  • Lee, Jae-Heun (Department of Pharmacology, College of Medicine, Institute of Health Sciences, Gyeongsang National University) ;
  • YunChoi, Hye-Sook (Natural Products Research Institute, Seoul National University) ;
  • Chang, Ki-Churl (Department of Pharmacology, College of Medicine, Institute of Health Sciences, Gyeongsang National University)
  • Published : 2004.10.21
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Abstract

Nitric oxide (NO) has been suggested to act as a mediator of cytokine-induced effects of turn over of bone. Activation of the inducible nitric oxide synthase (iNOS) by inflammation has been related with apoptotic cell death in osteoblast. YS 49, a synthetic isoquinoline alkaloid, inhibits NO production in macrophages activated with cytokines. In the present study, we investigated the molecular mechanism of YS 49 to inhibit iNOS expression in ROS 17/2.8 cells, which were activated with combined treatment of inflammatory cytokines $(TNF-{\alpha},\;IFN-{\gamma})$ and lipopolysaccharide (LPS). Results indicated that YS 49 concentration-dependently reduced iNOS mRNA and protein expression, as evidenced by Northern and Western blot analysis, respectively. The underlying mechanism by which YS 49 suppressed iNOS expression was not to affect iNOS mRNA stability but to inhibit activation and translocation of $NF-_kB$ by preventing the degradation of its inhibitory protein $I_kB_{\alpha}$. As expected, YS 49 prevented NO-induced apoptotic cell death by sodium nitroprusside. Taken together, it is concluded that YS 49 inhibits iNOS expression by interfering with degradation of phosphorylated inhibitory $_kB_{\alpha}\;(p-I_kB_{\alpha})$. These actions may be beneficial for the treatment of inflammation of the joint, such as rheumatoid arthritis.

Keywords

References

  1. Armour KJ, Armour KE, van't Hof RJ, Reid DM, Wei XQ, Liew FY, Ralston SH. Activation of the inducible nitric oxide synthase pathway contributes to inflammation-induced osteoporosis by suppressing bone formation and causing osteoblast apoptosis. Arthritis Rheum 44: 2790－2796, 2001 https://doi.org/10.1002/1529-0131(200112)44:12<2790::AID-ART466>3.0.CO;2-X
  2. Boileau C, Martel-Pelletier J, Moldovan F, Jouzeau JY, Netter P, Manning PT, Pelletier JP. The in situ up-regulation of chond- rocyte interleukin-1-converting enzyme and interleukin-18 levels in experimental osteoarthritis is mediated by nitric oxide. Arthritis Rheum 46: 2637－2647, 2002 https://doi.org/10.1002/art.10518
  3. Chae HJ, Chae SW, Kang JS, Bang BG, Cho SB, Park RK, So HS, Kim YK, Kim HM, Kim, HR. Dexamethasone suppresses tumor necrosis factor-alpha-induced apoptosis in osteoblasts: possible role for ceramide. Endocrinology 141: 2904－2913, 2000a https://doi.org/10.1210/en.141.8.2904
  4. Chae HJ, Kang JS, Byun JO, Han KS, Kim DU, Oh SM, Kim HM, Chae SW, Kim HR. Molecular mechanism of staurosporineinduced apoptosis in osteoblasts. Pharmacol Res 42: 373－381, 2000b https://doi.org/10.1006/phrs.2000.0700
  5. Farrell AJ, Blake DR, Palmer RMJ, Moncada S. Increased concentrations of nitrite in synovial fluid and serum samples suggest increased nitric oxide synthesis in rheumatic diseases. Ann Rheum Dis 51: 1219－1222, 1992 https://doi.org/10.1136/ard.51.11.1219
  6. Firestein GS, Yeo M, Zvaifler NJ. Apoptosis in rheumatoid arthritis synovium. J Clin Invest 96: 1631－1638, 1995 https://doi.org/10.1172/JCI118202
  7. Forstermann U, Kleinert H. Nitric oxide synthase: expression and expressional control of the three isoforms. Naunyn Schmiedebergs Arch Pharmacol 352: 351－364, 1995
  8. Fox SW, Chow JW. Nitric oxide synthase expression in bone cells. Bone 23: 1－6, 1998 https://doi.org/10.1016/S8756-3282(98)00070-2
  9. Grabowski PS, England AJ, Dykhuizen R, Copland M, Benjamin N, Reid DM, Ralston SH. Elevated nitric oxide production in rheumatoid arthritis. Detection using the fasting urinary nitrate: creatinine ratio. Arthritis Rheum 39: 643－647, 1996a https://doi.org/10.1002/art.1780390416
  10. Grabowski PS, Macpherson H, Ralston SH. Nitric oxide production in cells derived from the human joint. Br J Rheum 35: 207－212, 1996b https://doi.org/10.1093/rheumatology/35.3.207
  11. Grabowski PS, Wright PK, van't Hof RJ, Helfrich MH, Oshima H, Ralston SH. Immunolocalisation of inducible nitric oxide synthase in the synovium and cartilage in rheumatoid arthritis and osteoarthritis. Br J Rheumatol 36: 651－655, 1997 https://doi.org/10.1093/rheumatology/36.6.651
  12. Hilliquin P, Borderie D, Hernvann A, Menkes CJ, Ekindjian OG. Nitric oxide as S-nitrosoproteins in rheumatoid arthritis. Arthritis Rheum 40: 1512-1517, 1997. https://doi.org/10.1002/art.1780400820
  13. Hukkanen M, Hughes FJ, Buttery LD, Gross SS, Evans TJ, Seddon S, Riveros-Moreno V, Macintyre I, Polak JM. Cytokine-stimulated expression of inducible nitric oxide synthase by mouse, rat, and human osteoblast-like cells and its functional role in osteoblast metabolic activity. Endocrinology 136: 5445－5453, 1995 https://doi.org/10.1210/en.136.12.5445
  14. Ialenti A, Moncada S, Di Rosa M. Modulation of adjuvant arthritis by endogenous nitric oxide. Br J Pharmacol 110: 701－706, 1993 https://doi.org/10.1111/j.1476-5381.1993.tb13868.x
  15. Ihbe A, Baumann G, Heinzmann U, Atkinson MJ. Loss of the differentiated phenotype precedes apoptosis of ROS 17/2.8 osteoblast-like cells. Calcif Tissue Int 63: 208－213, 1998 https://doi.org/10.1007/s002239900516
  16. Jilka RL, Hangoc G, Girasole G, Passeri G, Williams DC, Abrams JS, Boyce B, Broxmeyer H, Manolagas SC. Increased osteoclast development after estrogen loss: mediation by interleukin-6. Science 257: 88－91, 1992 https://doi.org/10.1126/science.1621100
  17. Jilka RL, Weinstein RS, Bellido T, Parfitt AM, Manolagas SC. Osteoblast programmed cell death (apoptosis): modulation by growth factors and cytokines. J Bone Miner Res 13: 793－802, 1998 https://doi.org/10.1359/jbmr.1998.13.5.793
  18. Kang YJ, Koo EB, Lee YS, Yun-Choi HS, Chang KC.Prevention of the expression of inducible nitric oxide synthase by a novel positive inotropic agent, YS 49, in rat vascular smooth muscle and RAW 264.7 macrophages. Br J Pharmacol 128: 357－364, 1999a https://doi.org/10.1038/sj.bjp.0702787
  19. Kang YJ, Lee YS, Lee GW, Lee DH, Ryu JC, Yun-Choi HS, Chang KC. Inhibition of activation of nuclear factor kappaB is responsible for inhibition of inducible nitric oxide synthase expression by higenamine, an active component of aconite root. J Pharmacol Exp Ther 291: 314－320, 1999b
  20. Kang YJ, Seo SJ, Yun-Choi HS, Lee DH, Kim YM,Chang KC. A synthetic isoquinoline alkaloid, 1-(beta-naphthylmethyl)-6,7- dihydroxy-1,2,3,4-tetrahydroisoquinoline (YS 51), reduces inducible nitric oxide synthase expression and improves survival in a rodent model of endotoxic shock. J Pharmacol Exp Ther 301: 561－567, 2002 https://doi.org/10.1124/jpet.301.2.561
  21. Manolagas SC, Jilka RL. Mechanisms of disease: bone marrow, cytokines, and bone remodeling. Emerging insights into the pathophysiology of osteoporosis. N Engl J Med 332: 305－311, 1995 https://doi.org/10.1056/NEJM199502023320506
  22. McCartney-Francis N, Allen JB, Mizel DE, Albina JE, Xie QW, Nathan CF, Wahl SM. Suppression of arthritis by an inhibitor of nitric oxide synthase. J Exp Med 178: 749－754, 1993 https://doi.org/10.1084/jem.178.2.749
  23. Mogi M, Kinpara K, Kondo A, Togari A. Involvement of nitric oxide and biopterin in proinflammatory cytokine-induced apoptotic cell death in mouse osteoblastic cell line MC3T3-E1. Biochem Pharmacol 58: 649－654, 1999 https://doi.org/10.1016/S0006-2952(99)00131-8
  24. Mogi M, Kondo A, Kinpara K, Togari A. Anti-apoptotic action of nerve growth factor in mouse osteoblastic cell line. Life Sci 67: 1197－ 1206, 2000 https://doi.org/10.1016/S0024-3205(00)00705-0
  25. Murrell GA, Jang D, Williams RJ. Nitric oxide activates metalloprotease enzymes in articular cartilage. Biochem Biophys Res Commun 206: 15－21, 1995 https://doi.org/10.1006/bbrc.1995.1003
  26. Nakajima T, Aono H, Hasunuma T, Yamamoto K, Shirai T, Hirohata K, Nishioka K. Apoptosis and functional Fas antigen in rheumatoid arthritis synoviocytes. Arthritis Rheum 38: 485－ 491, 1995 https://doi.org/10.1002/art.1780380405
  27. Niederberger E, Tegeder I, Schafer C, Seegel M, Grosch S, Geisslinger G. Opposite effects of rofecoxib on nuclear factor-kappa B and activating protein-1 activation. J Pharmacol Exp Ther 304: 1153-1160, 2003. https://doi.org/10.1124/jpet.102.044016
  28. Palmer RM, Hickery MS, Charles IG, Moncada S, Bayliss MT. Induction of nitric oxide synthase in human chondrocytes. Biochem Biophys Res Commun 193: 398－405, 1993 https://doi.org/10.1006/bbrc.1993.1637
  29. Parfitt AM. Bone-forming cells in clinical conditions. In Bone. Volume 1: the osteoblast and osteocyte. BK Hall, editor. Telford Press and CRC Press. Boca Raton, FL 351－429, 1990
  30. Pelletier JP, Fernandes JC, Jovanovic DV, Reboul P, Martel- Pelletier J. Chondrocyte death in experimental osteoarthritis is nitric oxide synthase. J Rheumatol 11: 2509－2519, 2001
  31. Ralston SH, Grabowski PS. Mechanisms of cytokine induced bone resorption: Role of nitric oxide, cyclic guanosine monophosphate, and prostaglandins. Bone 19: 29－33, 1996 https://doi.org/10.1016/8756-3282(96)00101-9
  32. Ralston SH, Todd D, Helfrich M, Benjamin N, Grabowski PS. Human osteoblast-like cells produce nitric oxide and express inducible nitric oxide synthase. Endocrinology 135: 330－336, 1994 https://doi.org/10.1210/en.135.1.330
  33. Sakurai H, Kohsaka H, Liu MF, Higashiyama H, Hirata Y, Kanno K, Saito I, Miyasaka N. Nitric oxide production and inducible nitric oxide synthase expression in inflammatory arthritis. J Clin Invest 96: 2357－2363, 1995 https://doi.org/10.1172/JCI118292
  34. Sioud M, Mellbye O, Forre O. Analysis of the NF-kappa B p65 subunit, Fas antigen, Fas ligand and Bcl-2-related proteins in the synovium of RA and polyarticular JRA. Clin Exp Rheumatol 16: 125－134, 1998
  35. Stadler J, Stefanovic-Racic M, Billiar TR, Curran RD, McIntyre LA, Georgescu HI, Simmons RL, Evans CH. Articular chondrocytes synthesize nitric oxide in response to cytokines and lipopolysaccharide. J Immunol 147: 3915－3920, 1991
  36. Stefanovic-Racic M, Meyers K, Meschter C, Coffey JW, Hoffman RA, Evans CH. N-monomethyl arginine, an inhibitor of nitric oxide synthase, suppresses the development of adjuvant arthritis in rats. Arthritis Rheum 37: 1062－1069, 1994 https://doi.org/10.1002/art.1780370712
  37. Taskiran D, Stefanovic-Racic M, Georgescu H, Evans C. Nitric oxide mediates suppression of cartilage proteoglycan synthesis by interleukin-1. Biochem Biophys Res Commun 200: 142－148, 1994 https://doi.org/10.1006/bbrc.1994.1426
  38. Tom VK, Schotland S, Green J. Inflammatory cytokines (IL-1alpha, TNF-alpha) and LPS modulate the Ca$^{2+}$ signaling pathway in osteoblasts. Am J Physiol 274: C1686-1698, 1998 https://doi.org/10.1152/ajpcell.1998.274.6.C1686
  39. Wang E A, Rosen V, D'Alessandro JS, Beuduy M, Cordes P, Harada T, Israel DI, Hewick RM, Kerns KM, Lapan P, Luxenberg DP, Mcquaid D, Moutsatsos KI, Nove J, Wozney JM. Recombinant human bone morphogenetic protein induces bone formation. Proc Natl Acad Sci USA 87: 2220－2224, 1990. https://doi.org/10.1073/pnas.87.6.2220
  40. Wei XQ, Charles IG, Smith A, Ure J, Feng GJ, Huang FP, Xu D, Muller W, Moncada S, Liew FY. Altered immune response in mice lacking inducible nitric oxide synthase. Nature 375: 408－ 411, 1995 https://doi.org/10.1038/375408a0
  41. Weinstein RS, Jilka RL, Parfitt AM, Manolagas SC. Inhibition of osteoblastogenesis and promotion of apoptosis of osteoblasts and osteocytes by glucocorticoids: potential mechanisms of their deleterious effects on bone. J Clin Invest 102: 274－282, 1998 https://doi.org/10.1172/JCI2799
  42. Wetterwald A, Hoffstetter W, Cecchini MG, Lanske B, Wagner C, Fleisch H, Atkinson M. Characterization and cloning of the E11 antigen, a marker expression by rat osteoblasts and osteocytes. Bone 18: 125－132, 1996 https://doi.org/10.1016/8756-3282(95)00457-2
  43. Yamaguchi A, Katagiri T, Ikeda T, Wozney JM, Rosen V, Wang EA, Kahn AJ, Suda T, Yoshiki S. Recombinant human bone morphogenetic protein-2 stimulates osteoblastic maturation and inhibits myogenic differentiation in vitro. J Cell Biol 113: 681－ 687, 1991 https://doi.org/10.1083/jcb.113.3.681
  44. Yudoh K, Matsuno H, Nakazawa F, Katayama R, Kimura T. Recon stituting telomerase activity using the telomerase catalytic subunit prevents the telomere shorting and replicative senescence in human osteoblasts. J Bone Miner Res 16: 1453－1464, 2001 https://doi.org/10.1359/jbmr.2001.16.8.1453
  45. Yun-Choi HS, Pyo M K, Park KM, Chang KC, Lee DH. Antithrombotic effects of YS-49 and YS-51S-1-naphthylmethyl analogs of higenamine. Thromb Res 301: 561－567, 2001