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Cyclooxygenase-2 is involved in HIV-1 tat-induced inflammatory responses in the brain

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Abstract

Cyclooxygenase (COX)-2, a rate-limiting enzyme for prostanoid synthesis, can be involved in inflammatory-mediated cytotoxicity. Although the contribution of COX-2 to peripheral inflammation is well understood, its role in brain inflammation is not fully recognized. In particular, COX-2 involvement in inflammatory responses induced by HIV proteins in the central nervous system is not known. Therefore, the present study focused on COX-2 expression and its role in modulating the expression of brain inflammatory-related genes following exposure to the HIV-1 transactivating protein Tat. Intrahippocampal injections of Tat induced dose-dependent upregulation of COX-2 mRNA and protein levels in C57BL/6 mice. COX-2 immunoreactivity was primarily localized in microglial cells and astrocytes. Tat-induced COX-2 expression was partially prevented by pyrrolidine dithiocarbamate, a potent antioxidant and an inhibitor of the transcription factor, nuclear factor κB. Most importantly, administration of the COX-2 inhibitor NS-398 attenuated Tat-mediated upregulation of mRNA and protein expression of inflammatory mediators, such as monocyte chemoattractant protein-1, interleukin-1β, tumor necrosis factor-α, and inducible nitric oxide synthase. Moreover, treatment with NS-398 significantly attenuated Tat-induced activation of microglial cells. These results provide evidence that COX-2 overexpression can modulate induction of brain inflammatory mediators in response to HIV-1 Tat protein. Such alterations may play an important role in the development of brain inflammatory reactions in HIV-infected patients and contribute to the development of neurological complications in the course of HIV-1 infection.

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References

  • Beg A. A., Finco T. S., Nantermet P. V., and Baldwin A. S. Jr. (1993) Tumor necrosis factor and interleukin-1 lead to phosphorylation and loss of I kappa B alpha: a mechanism for NF-kappa B activation. Mol. Cell. Biol. 13, 3301–3310.

    PubMed  CAS  Google Scholar 

  • Blanco A. M., Pascual M., Valles S. L., and Guerri C. (2004) Ethanol-induced iNOS and COX-2 expression in cultured astrocytes via NF-kappa B. Neuroreport 15, 681–685.

    Article  PubMed  CAS  Google Scholar 

  • Bruce-Keller A. J., Barger S. W., Moss N. I., Pham J. T., Keller J. N., and Nath A. (2001) Pro-inflammatory and pro-oxidant properties of the HIV protein Tat in a microglial cell line: attenuation by 17 beta-estradiol. J. Neurochem. 78, 1315–1324.

    Article  PubMed  CAS  Google Scholar 

  • Bruce-Keller A. J., Chauhan A., Dimavuga F. O., Gee J., Keller J. N., and Nath A. (2003) Synaptic transport of human immunodeficiency virus-Tat protein causes neurotoxicity and gliosis in rat brain. J. Neurosci. 23, 8417–8422.

    PubMed  CAS  Google Scholar 

  • Caughey G. E., Pouliot M., Cleland L. G., and James M. J. (1997) Regulation of tumor necrosis factor-alpha and IL-1 beta synthesis by thromboxane A2 in nonadherent human monocytes. J. Immunol. 158, 351–358.

    PubMed  CAS  Google Scholar 

  • Chauhan A., Turchan J., Pocernich C. et al. (2003) Intracellular human immunodeficiency virus Tat expression in astrocytes promotes astrocyte survivol but induces potent neurotoxicity at distant sites via axonal transport. J. Biol. Chem. 278, 13512–13519.

    Article  PubMed  CAS  Google Scholar 

  • Corasamti M. T., Bellizzi C., Russo R., Colica C., Amantea D., and Di Renzo G. (2003) Caspase-1 inhibitors abolish deleterious enhancement of COX-2 expression induced by HIV-1 gp 120 in human neuroblastoma cells. Toxicol. Lett. 139, 213–219.

    Article  CAS  Google Scholar 

  • D'Aversa T. G., Yu K. O., and Berman J. W. (2004) Expression of chemokines by human fetal microglia after treatment with the human immunodeficiency virus type 1 protein Tat. J. Neurovirol. 10, 86–97.

    Article  PubMed  CAS  Google Scholar 

  • Engblom D., Ek M., Saha S., Ericsson-Dahlstrand A., Jakobsson P. J., and Blomqvist A. (2002) Prostaglandins as inflammatory messengers across the blood-brain barrier. J. Mol. Med. 80, 5–15.

    Article  PubMed  CAS  Google Scholar 

  • Ensoli B., Buonaguro L., Barillari G., et al. (1993) Release, up take, and effects of extracellular human immunodeficiency virus type 1 Tat protein on cell growth and viral transactivation. J. Virol. 67, 277–287.

    PubMed  CAS  Google Scholar 

  • Feuerstein G. Z., Wang X., and Barone F. C. (1997) Inflammatory gene expression in cerebral ischemia and trauma. Potential new therapeutic targets. Ann. N. Y. Acad. Sci. 825, 179–193.

    Article  PubMed  CAS  Google Scholar 

  • Flora G., Lee Y. W., Nath A., Hennig B., Marages W., and Toborek M. (2003) Methamphetamine potentiates HIV-1 Tat protein-mediated activation of redox-sensitive pathways in discrete regions of the brain. Exp. Neurol. 179, 60–70.

    Article  PubMed  CAS  Google Scholar 

  • Futaki N., Yoshikawa K., Hamasaka Y., et al. (1993) NS-398, a novel non-steroidal anti-inflammatory drug with potent analgesic and antipyretic effects, which causes minimal stomach lesions. Gen. Pharmacol. 24, 105–110.

    PubMed  CAS  Google Scholar 

  • Griffin D. E., Wesselingh S. L., and McArthur J. C. (1994) Elevated centralnervous system prostaglandins in human immunodeficiency virus-associated dementia. Ann. Neurol. 35, 592–597.

    Article  PubMed  CAS  Google Scholar 

  • Hara K., Kong D. L., Sharp F. R., and Weinstein P. R. (1998) Effect of selective inhibition of cyclooxygenase 2 on temporary focal cerebral ischemia in rats. Neurosci. Lett. 256, 53–56.

    Article  PubMed  CAS  Google Scholar 

  • Haughey N. J., and Mattson M. P. (2002) Calcium dysregulation and neuronal apoptosis by the HIV-1 proteins Tat and gp 120. J. Acquir. Immune Derv. Syndr. 31(Suppl 2), S55-S61.

    CAS  Google Scholar 

  • Hoozemans J. J., Veerhuis R., Janssen I., van Elk E. H. Rozemuller A. J., and Eikelenboom P. (2002) The role of cyclo-oxygenase 1 and 2 activity in prostaglandin E(2) secretion by cultured human adult microglia: implications for Alzheimer's disease. Brain Res. 951, 218–226.

    Article  PubMed  CAS  Google Scholar 

  • Hudson L., Liu J., Nath A., et al. (2000) Detection of the human immunodeficiency virus regulatory protein tat in CNS tissues. J. Neurovirol. 6, 145–155.

    PubMed  CAS  Google Scholar 

  • Huigen M. C., Kamp W., and Nottet H. S. (2004) Multiple effects of HIV-1 trans-activator protein on the pathogenesis of HIV-1 infection. Eur. J. Clin. Invest. 34, 57–66.

    Article  PubMed  CAS  Google Scholar 

  • Hurley S. D., Olschowka J. A., and O'Banion M. K. (2002) Cyclooxygenase inhibition as a strategy to ameliorate brain injury. J. Neurotrauma 19, 1–15.

    Article  PubMed  Google Scholar 

  • Israel N. and Gougerot-Pocidalo M. A. (1997) Oxidativestress in human immunodeficiency virus infection. Cell. Mol. Life Sci. 53, 864–870.

    Article  PubMed  CAS  Google Scholar 

  • Khan N. A., Di Cello F., Nath A., and Kim K. S. (2003) Human immunodeficiency virus type 1 tat-mediated cytotoxicity of human brain microvascular endothelial cells. J. Neurovirol. 9, 584–593.

    PubMed  CAS  Google Scholar 

  • Khurdayan V. K., Buch S., El-Hage N., et al. (2004) Preferential vulnerability of astroglia and glial precursors to combined opioid and HIV-1 Tat exposure in vitro. Eur. J. Neurosci. 19, 3171–3182.

    Article  PubMed  Google Scholar 

  • Kim T. A., Avraham H. K., Koh Y. H., Jiang S., Park I. W., and Avraham S. (2003) HIV-1 Tat-mediated apoptosis in human brain microvascular endothelial cells. J. Immunol. 170, 2629–2637.

    PubMed  CAS  Google Scholar 

  • Kruman I. I., Nath A., and Mattson M. P. (1998) HIV-1 protein Tat induces apoptosis of hippocampal neurons by a mechanism involving caspase activation, calcium overload, and oxidative stress. Exp. Neurol. 154, 276–288.

    Article  PubMed  CAS  Google Scholar 

  • Kruman I. I., Nath A., Maragos W. F., et al. (1999) Evidence that Par-4 participates in the pathogenesis of HIV encephalitis. Am. J. Pathol. 155, 39–46.

    PubMed  CAS  Google Scholar 

  • Kyrkanides S., Moore A. H., Olschowka J. A., et al. (2002) Cyclooxygenase-2 modulates brain inflammation-related gene expression in central nervous system radiation injury. Brain Res. Mol. Brain Res. 106, 159–169.

    Article  Google Scholar 

  • Liu Q. N., Reddy S., Sayre J. W., Pop V., Graves M. C., and Fiala M. (2001) Essential role of HIV type 1-infected and cyclooxygenase 2-activated macrophages and T cells in HIV type 1 myocarditis. AIDS Res. Hum. Retroviruses 17, 1423–1433.

    Article  PubMed  CAS  Google Scholar 

  • Liu X., Jana M., Dasgupta S., et al. (2002) Human immunodeficiency virus type 1 (HIV-1) tat induces nitric-oxide synthase in human astroglia. J. Biol. Chem. 277, 39,312–39,319.

    CAS  Google Scholar 

  • Ma M. and Nath A. (1997) Molecular determinants for cellular uptake of Tat protein of human immunodeficiency virus type 1 in brain cells. J. Virol. 71, 2495–2499.

    PubMed  CAS  Google Scholar 

  • Madrigal J. L., Garcia-Bueno B., Moro M. A., Lizasoain L., Lorenzo P., and Leza J. C. (2003) Relationship between cyclooxygenase-2 and nitric oxide synthase-2 in rat cortex after stress. Eur. J. Neurosci. 18, 1701–1705.

    Article  PubMed  Google Scholar 

  • Madrigal J. L., Caso J. R., de Cristobal J., et al. (2003) Effect of subacute and chronic immobilisation stress on the outcome of permanent focal cerebral ischaemia in rats. Brain Res. 979, 137–145.

    Article  PubMed  CAS  Google Scholar 

  • Magnuson D. S., Knudsen B. E., Geiger J. D., Brownstone R. M., and Nath A. (1995) Human immunodeficiency virus type 1 tat activates non-N-methyl-D-aspartate excitatory amino acid receptors and causes neurotoxicity. Ann. Neurol. 37, 373–380.

    Article  PubMed  CAS  Google Scholar 

  • Masferrer J. L., Zweifel B. S., Manning P. T., et al. (1994) Selective inhibition of inducible cyclooxygenase 2 in vivo is antiinflammatory and nonulcerogenic. Proc. Natl. Acad. Sci. USA 91, 3228–3232.

    Article  PubMed  CAS  Google Scholar 

  • Matzen K., Dirkx A. E., oude Egbrink M. G., et al. (2004) HIV-1 Tat increases the adhesion of monocytes and T-cells to the endothelium in vitro and in vivo: implications for AIDS-associated vasculopathy. Virus Res. 104, 145–155.

    Article  PubMed  CAS  Google Scholar 

  • Minghetti L., Visentin S., Patrizio M., Franchini L., Ajmone-Cat M. A., and Levi G. (2004) Multiple actions of the human immunodeficiency virus type-1 Tat protein on microglial cell functions. Neurochem. Res. 29, 965–978.

    Article  PubMed  CAS  Google Scholar 

  • Monaco C. and Paleolog E. (2004) Nuclear factor kappaB: a potential therapeutic target in atherosclerosis and thrombosis. Cardiovasc. Res. 61, 671–682.

    Article  PubMed  CAS  Google Scholar 

  • Nabel G. and Baltimore D. (1987) An inducible transcription factor activates expression of human immunodeficiency virus in T cells. Nature 326, 711–713.

    Article  PubMed  CAS  Google Scholar 

  • Nath A., Conant K., Chen P., Scott C., and Major E. O. (1999) Transient exposure to HIV-1 Tat protein results in cytokine production in macrophages and astrocytes. A hit and run phenomenon. J. Biol. Chem. 274, 17,098–17,102.

    Article  CAS  Google Scholar 

  • Nath A., Psooy K., Martin C., et al. (1996) Identification of a human immunodeficiency virus type 1 Tat epitope that is neuroexcitatory and neurotoxic. J. Virol. 70, 1475–1480.

    PubMed  CAS  Google Scholar 

  • New D. R., Ma M., Epstein L. G., Nath A., and Gelbard H. A. (1997) Human immunodeficiency virus type 1 Tat protein induces death by apoptosis in primary human neuron cultures. J. Neurovirol. 3, 168–173.

    Article  PubMed  CAS  Google Scholar 

  • Nogawa S., Zhang F., Ross M. E., and Iadecola C. (1997) Cyclo-oxygenase-2 gene expression in neurons contributes to ischemic brain damage. J. Neurosci. 17, 2746–2755.

    PubMed  CAS  Google Scholar 

  • Nottet H. S. (1999) Interactions between macrophages and brain microvascular endothelial cells: role in pathogenesis of HIV-1 infection and blood-crain barrier function. J. Neurovirol. 5, 659–669.

    PubMed  CAS  Google Scholar 

  • Pereira C. F., Boven L. A., Middel J., Verhoef J., and Nottet H. S. (2000) Induction of cyclooxygenase-2 expression during HIV-1-infected monocyte-derived macrophage and human brain microvascular endothelial cell interactions. J. Leukoc. Biol. 68, 423–428.

    PubMed  CAS  Google Scholar 

  • Petito C. K., Roberts B., Cantando J. D., Rabinstein A., and Duncan R. (2001) Hippocampal injury and alterations in neuronal chemokine co-receptor expression in patients with AIDS. J. Neuropathol. Exp. Neurol. 60, 377–385.

    PubMed  CAS  Google Scholar 

  • Poligone B. and Baldwin A. S. (2001) Positive and negative regulation of NF-kappaB by COX-2: roles of different prostaglandins. J. Biol. Chem. 276, 38,658–38,664.

    Article  CAS  Google Scholar 

  • Pu H., Tian J., Flora G., et al. (2003) HIV-1 Tat protein upregulates inflammatory mediators and induces monocyte invasion into the brain. Mol. Cell. Neurosci. 24, 224–237.

    Article  PubMed  CAS  Google Scholar 

  • Rose J. W., Hill K. E., Watt H. E., and Carlson N. G. (2004) Inflammatory cell expression of cyclooxygenase-2 in the multiple sclerosis lesion. J. Neuroimmunol. 149, 40–49.

    Article  PubMed  CAS  Google Scholar 

  • Shor Posner G. (2000) Cognitive function in HIV-1-infected drug users. J. Acquir. Immune. Defic. Syndr. 25(Suppl 1), S70-S73.

    Article  PubMed  Google Scholar 

  • Sugimoto K. and Iadecola C. (2003) Delayed effect of administration of COX-2 inhibitor in mice with acute cerebral ischemia. Brain Res. 960, 273–276.

    Article  PubMed  CAS  Google Scholar 

  • Tanabe T. and Tohnai N. (2002) Cyclooxygenase isozymes and their gene structures and expression. Prostaglandins Other Lipid Mediat. 68–69, 95–114.

    Article  PubMed  Google Scholar 

  • Toborek M., Lee Y. W., Kaiser S., and Hennig B. (2002) Measurement of inflammatory properties of fatty acids in human endothelial cells. Methods Enzymol. 352, 198–219.

    Article  PubMed  CAS  Google Scholar 

  • Toborsk M., Lee, Y. W., Pu, H., et al. (2003) HIV-Tat protein induces oxidative and inflammatory pathways in brain endothelium. J. Neurochem. 84, 169–179.

    Article  Google Scholar 

  • Torres-Munoz J., Stockton, P., Tacoronte N., Roberts B., Maronpot R. R., and Petito C. K. (2001) Detection of HIV-1 gene sequences in hippocampal neurons isolated from postmortem AIDS brains by laser capture microdissection. J. Neuropathol. Exp. Neurol. 60, 885–892.

    PubMed  CAS  Google Scholar 

  • Valle L. D., Croul S., Morgello S., Amini S., Rappaport J., and Khalili K. (2000) Detection of HIV-1 Tat and JCV capsid protein, VP1, in AIDS brain with progressive multifocal leukoencephalopathy. J. Neurovirol. 6, 221–228.

    PubMed  CAS  Google Scholar 

  • Vives E., Richard J. P., Rispal C., and Lebleu B. (2003) TAT peptide internalization: seeking the mechanism of entry. Curr. Protein Pept. Sci. 4, 125–132.

    Article  PubMed  CAS  Google Scholar 

  • Warner T. D. and Mitchell J. A. (2004) Cyclooxygenases: new forms, new inhibitors, and lessons from the clinic. FASEB J. 18, 790–804.

    Article  PubMed  CAS  Google Scholar 

  • Woodman S. E., Benveniste E. N., Nath A., and Berman J. W. (1999) Human immunodeficiency virus type 1 TAT protein induces adhesion molecule expression in astrocytes. J. Neurovirol 5, 678–684.

    PubMed  CAS  Google Scholar 

  • Wang T., Qin L., Liu B., et al. (2004) Role of reactive oxygen species in LPS-induced production of prostaglandin E2 in microglia. J. Neurochem. 88, 939–947.

    Article  PubMed  CAS  Google Scholar 

  • Wu K. K. (2003) Control of COX-2 and iNOS gene expressions by aspirin and salicylate. Thromb. Res. 110, 273–276.

    Article  PubMed  CAS  Google Scholar 

  • Wu R. F., Gu Y., Xu Y. C., Mitola S., Bussolino F., and Terada L. S. (2004) Human immunodeficiency virus type 1 Tat regulates endothelial cell actin cytoskeletal dynamics through PAK1 activation and oxidant production. J. Virol. 78, 779–789.

    Article  PubMed  CAS  Google Scholar 

  • Zink W. E., Anderson E., Boyle J., et al. (2002) Impaired spatial cognition and synaptic potentiation in a murine model of human immunodeficiency virus type 1 encephalitis. J. Neurosci. 22, 2096–2105.

    PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Molecular Neuroscience and Vascular Biology Laboratory, Department of Surgery, University of Kentucky, 40536, Lexington, KY

    Govinder Flora, Hong Pu & Michal Toborek

  2. College of Agriculture, University of Kentucky, 40536, Lexington, KY

    Bernhard Hennig

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  1. Govinder Flora
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  2. Hong Pu
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  3. Bernhard Hennig
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  4. Michal Toborek
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Correspondence to Michal Toborek.

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Flora, G., Pu, H., Hennig, B. et al. Cyclooxygenase-2 is involved in HIV-1 tat-induced inflammatory responses in the brain. Neuromol Med 8, 337–351 (2006). https://doi.org/10.1385/NMM:8:3:337

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  • DOI: https://doi.org/10.1385/NMM:8:3:337

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