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Down-regulation of inducible nitric oxide synthase by lysophosphatidic acid in human respiratory epithelial cells

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Abstract

Viral infection generally results in the activation of inducible nitric oxide synthase (iNOS or NOS2) in respiratory epithelial cells by inflammatory cytokines. Activated NOS2 catalyzes synthesis of nitric oxide (NO), which in excess can cause cellular injury. On the other hand, lysophosphatidic acid (LPA), a lipid mediator released from epithelial cells, platelets, and fibroblasts in injured tissue, functions in repair of cell injury. However, details of the mechanism for repair by LPA remain unknown. We demonstrated one effect of LPA favoring repair, specifically inhibition by LPA of cytokine-induced NOS2 protein and mRNA expression by human respiratory epithelial cells in vitro. NO production by LPA-treated, cytokine-stimulated cells was also reduced. These decreases were prevented by Rho kinase inhibition with Y-27632. Thus, down-regulation by LPA of cytokine-induced increases in NOS2 activity is likely to involve a Rho-dependent signaling pathway. Harmful biologic effects of NO in viral respiratory infection might be modified by therapeutic manipulations involving LPA or Rho. (Mol Cell Biochem 262: 51–59, 2004)

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References

  1. Hayden FG, Fritz R, Lobo MC, Alvord W, Strober W, Straus SE: Local and systemic cytokine responses during experimental human influenza A virus infection. Relation to symptom formation and host defense. J Clin Invest 101: 643–649, 1998

    PubMed  Google Scholar 

  2. Matsukura S, Kokubu F, Kubo H, Tomita T, Tokunaga H, Kadokura M, Yamamoto T, Kuroiwa Y, Ohno T, Suzaki H, Adachi M: Expression of RANTES by normal airway epithelial cells after influenza virus A infection. Am J Respir Cell Mol Biol 18: 255–264, 1998

    PubMed  Google Scholar 

  3. Julkunen I, Melen K, Nyqvist M, Pirhonen J, Sareneva T, Matikainen S: Inflammatory responses in influenza A virus infection. Vaccine 19(suppl 1):S32–S37, 2000

    Google Scholar 

  4. Adachi M, Matsukura S, Tokunaga H, Kokubu F: Expression of cytokines on human bronchial epithelial cells induced by influenza virus A. Int Arch Allergy Immunol 113: 307–311, 1997

    PubMed  Google Scholar 

  5. Julkunen I, Sareneva T, Pirhonen J, Ronni T, Melen K, Matikainen S: Molecular pathogenesis of influenzaAvirus infection and virus-induced regulation of cytokine gene expression. Cytokine Growth Factor Rev 12: 171–180, 2001

    Google Scholar 

  6. Van Reeth K: Cytokines in the pathogenesis of influenza. Vet Microbiol 74: 109–116, 2000

    Article  PubMed  Google Scholar 

  7. Karupiah G, Xie QW, Buller RM, Nathan C, Duarte C, MacMicking JD: Inhibition of viral replication by interferon-gamma-induced nitric oxide synthase. Science 261: 1445–1448, 1993

    PubMed  Google Scholar 

  8. Croen KD: Evidence for antiviral effect of nitric oxide. Inhibition of herpes simplex virus type 1 replication. J Clin Invest 91: 2446–2452, 1993

    PubMed  Google Scholar 

  9. Mannick JB, Asano K, Izumi K, Kieff E, Stamler JS: Nitric oxide produced by human B lymphocytes inhibits apoptosis and Epstein-Barr virus reactivation. Cell 79: 1137–1146, 1994

    PubMed  Google Scholar 

  10. Zaragoza C, Ocampo CJ, Saura M, McMillan A, Lowenstein CJ: Nitric oxide inhibition of coxsackievirus replication in vitro. J Clin Invest 100: 1760–1767, 1997

    PubMed  Google Scholar 

  11. Fang FC: Perspectives series: Host/pathogen interactions. Mechanisms of nitric oxide-related antimicrobial activity. J Clin Invest 99: 2818–2825, 1997

    PubMed  Google Scholar 

  12. Toews ML, Ediger TL, Romberger DJ, Rennard SI: Lysophosphatidic acid in airway function and disease. Biochim Biophys Acta 1582: 240–250, 2002

    Article  PubMed  Google Scholar 

  13. Uetani K, Der SD, Zamanian-Daryoush M, de La Motte C, Lieberman BY, Williams BR, Erzurum SC: Central role of double-stranded RNAactivated protein kinase in microbial induction of nitric oxide synthase. J Immunol 165: 988–996, 2000

    PubMed  Google Scholar 

  14. Nicholson S, Bonecini-Almeida Mda G, Lapa e Silva JR, Nathan C, Xie QW, Mumford R, Weidner JR, Calaycay J, Geng J, Boechat N, et al.: Inducible nitric oxide synthase in pulmonary alveolar macrophages from patients with tuberculosis. J Exp Med 183: 2293–2302, 1996

    Article  PubMed  Google Scholar 

  15. Chikumi H, Fukuhara S, Gutkind JS: Regulation of G protein-linked guanine nucleotide exchange factors for Rho, PDZ-RhoGEF, and LARG by tyrosine phosphorylation: Evidence of a role for focal adhesion kinase. J Biol Chem 277: 12463–12473, 2002

    Article  PubMed  Google Scholar 

  16. Misko TP, Schilling RJ, Salvemini D, Moore WM, Currie MG: A fluorometric assay for the measurement of nitrite in biological samples. Anal Biochem 214: 11–16, 1993

    Article  PubMed  Google Scholar 

  17. Jalink K, Hordijk PL, Moolenaar WH: Growth factor-like effects of lysophosphatidic acid, a novel lipid mediator. Biochim Biophys Acta 1198: 185–196, 1994

    Article  PubMed  Google Scholar 

  18. Guo FH, Uetani K, Haque SJ, Williams BR, Dweik RA, Thunnissen FB, Calhoun W, Erzurum SC: Interferon gamma and interleukin 4 stimulate prolonged expression of inducible nitric oxide synthase in human airway epithelium through synthesis of soluble mediators. J Clin Invest 100: 829–838, 1997

    PubMed  Google Scholar 

  19. Guo FH, Comhair SA, Zheng S, Dweik RA, Eissa NT, Thomassen MJ, Calhoun W, Erzurum SC: Molecular mechanisms of increased nitric oxide (NO) in asthma: Evidence for transcriptional and posttranslational regulation of NO synthesis. J Immunol 164: 5970–5980, 2000

    PubMed  Google Scholar 

  20. Marks-Konczalik J, Chu SC, Moss J: Cytokine-mediated transcriptional induction of the human inducible nitric oxide synthase gene requires both activator protein 1 and nuclear factor kappaB-binding sites. J Biol Chem 273: 22201–22208, 1998

    Article  PubMed  Google Scholar 

  21. Delarue FL, Taylor BS, Sebti SM: Ras and RhoA suppress whereas RhoB enhances cytokine-induced transcription of nitric oxide synthase-2 in human normal liver AKN-1 cells and lung cancer A-549 cells. Oncogene 20: 6531–6537, 2001

    Article  PubMed  Google Scholar 

  22. Bhat NR, Zhang P, Lee JC, Hogan EL: Extracellular signal-regulated kinase and p38 subgroups of mitogen-activated protein kinases regulate inducible nitric oxide synthase and tumor necrosis factor-alpha gene expression in endotoxin-stimulated primary glial cultures. J Neurosci 18: 1633–1641, 1998

    PubMed  Google Scholar 

  23. Pahan K, Sheikh FG, Khan M, Namboodiri AM, Singh I: Sphingomyelinase and ceramide stimulate the expression of inducible nitric-oxide synthase in rat primary astrocytes. J Biol Chem 273: 2591–2600, 1998

    Article  PubMed  Google Scholar 

  24. Singh K, Balligand JL, Fischer TA, Smith TW, Kelly RA: Regulation of cytokine-inducible nitric oxide synthase in cardiac myocytes and microvascular endothelial cells. Role of extracellular signal-regulated kinases 1 and 2 (ERK1/ERK2) and STAT1 alpha. J Biol Chem 271: 1111–1117, 1996

    Article  PubMed  Google Scholar 

  25. Tanaka K, Nakazawa H, Okada K, Umezawa K, Fukuyama N, Koga Y: Nitric oxide mediates murine cytomegalovirus-associated pneumonitis in lungs that are free of the virus. J Clin Invest 100: 1822–1830, 1997

    PubMed  Google Scholar 

  26. Akaike T, Noguchi Y, Ijiri S, Setoguchi K, Suga M, Zheng YM, Dietzschold B, Maeda H: Pathogenesis of influenza virus-induced pneumonia: Involvement of both nitric oxide and oxygen radicals. Proc Natl Acad Sci USA 93: 2448–2453, 1996

    PubMed  Google Scholar 

  27. Bogdan C: Nitric oxide and the immune response. Nat Immunol 2: 907–916, 2001

    PubMed  Google Scholar 

  28. Hashimoto T, Yamashita M, Ohata H, Momose K: Lysophosphatidic acid enhances in vivo infiltration and activation of guinea pig eosinophils and neutrophils via a Rho/Rho-associated protein kinase-mediated pathway. J Pharmacol Sci 91: 8–14, 2003

    Article  PubMed  Google Scholar 

  29. Holtsberg FW, Steiner MR, Bruce-Keller AJ, Keller JN, Mattson MP, Moyers JC, Steiner SM: Lysophosphatidic acid and apoptosis of nerve growth factor-differentiated PC12 cells. J Neurosci Res 53: 685–696, 1998

    Article  PubMed  Google Scholar 

  30. Hall A: Rho GTPases and the actin cytoskeleton. Science 279: 509–514, 1998

    Article  PubMed  Google Scholar 

  31. Sahai E, Marshall CJ: RHO-GTPases and cancer. Nat Rev Cancer 2: 133–142, 2002

    Article  PubMed  Google Scholar 

  32. Boettner B, Van Aelst L: The role of Rho GTPases in disease development. Gene 286: 155–174, 2002

    Article  PubMed  Google Scholar 

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Authors and Affiliations

  1. Division of Internal Medicine and Molecular Therapeutics, Department of Multidisciplinary Internal Medicine, Tottori University, Japan

    Saori Kadowaki

  2. Division of Internal Medicine and Molecular Therapeutics, Department of Multidisciplinary Internal Medicine, Japan

    Hiroki Chikumi, Hiroyuki Yamamoto, Kazuhiko Yoneda, Akira Yamasaki & Eiji Shimizu

  3. Division of Molecular Biology, Department of Molecular and Cellular Biology, Faculty of Medicine, Tottori University, Japan

    Saori Kadowaki & Kenzo Sato

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  1. Saori Kadowaki
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  2. Hiroki Chikumi
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  4. Kazuhiko Yoneda
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Kadowaki, S., Chikumi, H., Yamamoto, H. et al. Down-regulation of inducible nitric oxide synthase by lysophosphatidic acid in human respiratory epithelial cells. Mol Cell Biochem 262, 51–59 (2004). https://doi.org/10.1023/B:MCBI.0000038215.89821.7f

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  • DOI: https://doi.org/10.1023/B:MCBI.0000038215.89821.7f

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