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Synergistic expression of inducible nitric oxide synthase by phorbol ester and interferon-gamma is mediated through NF-kappaB and ERK in microglial cells.

Abstract

A proinflammatory cytokine IFN-gamma stimulates microglia in the injured brain; however, signaling pathways for IFN-gamma-mediated microglia activation are not well characterized. In the present study, a protein kinase C (PKC) activator phorbol 12-myristate 13-acetate (PMA) acts in concert with IFN-gamma to enhance nitric oxide (NO) production in murine microglial BV2 cells by synergistically increasing expression of inducible NO synthase (iNOS). The synergistic NO production by PMA was in part decreased by a PKC inhibitor Gö6976. PMA alone induced activation of nuclear factor-kappa B (NF-kappaB) and extracellular signal-regulated kinase (ERK) of mitogen-activated protein kinases (MAPKs) subtypes, whereas IFN-gamma alone had little effect. PMA and IFN-gamma synergistically enhanced activity of NF-kappaB, but not ERK. The inhibitors of NF-kappaB (pyrrolidine dithiocarbamate, PDTC) and ERK (1,4-diamino-2,3-dicyano-1,4 bis[2-aminophenylthio]butadiene; U0126) markedly decreased synergistic NO production in BV2 cells treated with IFN-gamma and PMA in combination. We found further that co-treatment with IFN-gamma and PMA synergistically induced interferon regulatory factor-1 (IRF-1), which is the major transcription factor for IFN-gamma-mediated iNOS expression. The present results demonstrate the cooperative interaction of multiple signaling pathways in the induction of NO production in activated microglial cells, and suggest that the functional interplay of these pathways may be important for the onset of microglia-mediated inflammatory responses in brain.

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  • Authors+Show Affiliations

    ,

    Research Institute, National Cancer Center, Goyang, Gyeonggi, Republic of Korea.

    , , ,

    Source

    Journal of neuroscience research 73:5 2003 Sep 01 pg 659-69

    MeSH

    Animals
    Cell Line
    DNA-Binding Proteins
    Drug Synergism
    Enzyme Inhibitors
    Gene Expression
    Immunoblotting
    Interferon Regulatory Factor-1
    Interferon-gamma
    Mice
    Microglia
    Mitogen-Activated Protein Kinases
    NF-kappa B
    Nitric Oxide
    Nitric Oxide Synthase
    Nitric Oxide Synthase Type II
    Phosphoproteins
    RNA, Messenger
    Reverse Transcriptase Polymerase Chain Reaction
    Signal Transduction
    Tetradecanoylphorbol Acetate

    Pub Type(s)

    Journal Article
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    12929133

    Citation

    Han, Inn-Oc, et al. "Synergistic Expression of Inducible Nitric Oxide Synthase By Phorbol Ester and Interferon-gamma Is Mediated Through NF-kappaB and ERK in Microglial Cells." Journal of Neuroscience Research, vol. 73, no. 5, 2003, pp. 659-69.
    Han IO, Kim HS, Kim HC, et al. Synergistic expression of inducible nitric oxide synthase by phorbol ester and interferon-gamma is mediated through NF-kappaB and ERK in microglial cells. J Neurosci Res. 2003;73(5):659-69.
    Han, I. O., Kim, H. S., Kim, H. C., Joe, E. H., & Kim, W. K. (2003). Synergistic expression of inducible nitric oxide synthase by phorbol ester and interferon-gamma is mediated through NF-kappaB and ERK in microglial cells. Journal of Neuroscience Research, 73(5), pp. 659-69.
    Han IO, et al. Synergistic Expression of Inducible Nitric Oxide Synthase By Phorbol Ester and Interferon-gamma Is Mediated Through NF-kappaB and ERK in Microglial Cells. J Neurosci Res. 2003 Sep 1;73(5):659-69. PubMed PMID: 12929133.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Synergistic expression of inducible nitric oxide synthase by phorbol ester and interferon-gamma is mediated through NF-kappaB and ERK in microglial cells. AU - Han,Inn-Oc, AU - Kim,Hee-Sun, AU - Kim,Hyoung-Chun, AU - Joe,Eun-Hye, AU - Kim,Won-Ki, PY - 2003/8/21/pubmed PY - 2003/10/15/medline PY - 2003/8/21/entrez SP - 659 EP - 69 JF - Journal of neuroscience research JO - J. Neurosci. Res. VL - 73 IS - 5 N2 - A proinflammatory cytokine IFN-gamma stimulates microglia in the injured brain; however, signaling pathways for IFN-gamma-mediated microglia activation are not well characterized. In the present study, a protein kinase C (PKC) activator phorbol 12-myristate 13-acetate (PMA) acts in concert with IFN-gamma to enhance nitric oxide (NO) production in murine microglial BV2 cells by synergistically increasing expression of inducible NO synthase (iNOS). The synergistic NO production by PMA was in part decreased by a PKC inhibitor Gö6976. PMA alone induced activation of nuclear factor-kappa B (NF-kappaB) and extracellular signal-regulated kinase (ERK) of mitogen-activated protein kinases (MAPKs) subtypes, whereas IFN-gamma alone had little effect. PMA and IFN-gamma synergistically enhanced activity of NF-kappaB, but not ERK. The inhibitors of NF-kappaB (pyrrolidine dithiocarbamate, PDTC) and ERK (1,4-diamino-2,3-dicyano-1,4 bis[2-aminophenylthio]butadiene; U0126) markedly decreased synergistic NO production in BV2 cells treated with IFN-gamma and PMA in combination. We found further that co-treatment with IFN-gamma and PMA synergistically induced interferon regulatory factor-1 (IRF-1), which is the major transcription factor for IFN-gamma-mediated iNOS expression. The present results demonstrate the cooperative interaction of multiple signaling pathways in the induction of NO production in activated microglial cells, and suggest that the functional interplay of these pathways may be important for the onset of microglia-mediated inflammatory responses in brain. SN - 0360-4012 UR - https://www.unboundmedicine.com/medline/citation/12929133/Synergistic_expression_of_inducible_nitric_oxide_synthase_by_phorbol_ester_and_interferon_gamma_is_mediated_through_NF_kappaB_and_ERK_in_microglial_cells_ L2 - https://doi.org/10.1002/jnr.10706 DB - PRIME DP - Unbound Medicine ER -