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IL-1beta, an immediate early protein secreted by activated microglia, induces iNOS/NO in C6 astrocytoma cells through p38 MAPK and NF-kappaB pathways.

Abstract

In the present study we sought to examine cell-cell interactions by investigating the effects of factors released by stimulated microglia on inducible nitric oxide (NO) synthase (iNOS) induction in astrocytoma cells. After examining the temporal profiles of proinflammatory molecules induced by lipopolysaccharide (LPS) stimulation in BV2 microglial cells, iNOS and IL-1beta were observed to be the first immediate-response molecules. Removal of LPS after 3 hr stimulation abrogated NO release, whereas a full induction of IL-1beta was retained in BV2 cells. We observed consistently that conditioned medium (CM) from activated microglia resulted in the induction of iNOS in C6 cells, and IL-1beta was shown to be a key regulator of iNOS induction. An IL-1beta-neutralizing antibody diminished NO induction. Incubation with recombinant IL-1beta stimulated NO release to a lesser extent compared to microglial CM; co-treatment of LPS and IL-1beta had a potent, synergistic effect on NO release from C6 cells. Transient transfection with MEK kinase 1 (MEKK1) or nuclear factor-kappa B (NF-kappaB) expression plasmids induced iNOS, and IL-1beta further enhanced the MEKK1 response. Furthermore, IL-1beta-mediated NO release from C6 cells was significantly suppressed by inhibition of p38 mitogen activated protein kinase (MAPK) or NF-kappaB by specific chemical inhibitors. Both IL-1beta and MEKK1 stimulated p38 and JNK MAPKs, as well as the NF-kappaB pathway, to induce iNOS in C6 cells. Microglia may represent an anti-tumor response in the central nervous system, which is potentiated by the local secretion of immunomodulatory factors that in turn affects astrocytoma (glioma) cells. A better understanding of microglia-glioma or microglia-astrocyte interactions will help in the design of novel immune-based therapies for brain tumors or neuronal diseases.

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  • Authors+Show Affiliations

    ,

    Department of Physiology and Biophysics, and Center for Advanced Medical Education by BK21 Project, Inha University, College of Medicine, Incheon, Korea.

    , , ,

    Source

    Journal of neuroscience research 84:5 2006 Oct pg 1037-46

    MeSH

    Analysis of Variance
    Animals
    Animals, Newborn
    Astrocytoma
    Blotting, Western
    Cells, Cultured
    Electrophoretic Mobility Shift Assay
    Enzyme Activation
    Enzyme Inhibitors
    Interleukin-1beta
    Lipopolysaccharides
    Mice
    Microglia
    NF-kappa B
    Nitric Oxide
    Nitric Oxide Synthase Type II
    RNA, Messenger
    Rats
    Rats, Sprague-Dawley
    Reverse Transcriptase Polymerase Chain Reaction
    Signal Transduction
    Transfection
    p38 Mitogen-Activated Protein Kinases

    Pub Type(s)

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

    Language

    eng

    PubMed ID

    16881054

    Citation

    Kim, Yun-Jung, et al. "IL-1beta, an Immediate Early Protein Secreted By Activated Microglia, Induces iNOS/NO in C6 Astrocytoma Cells Through P38 MAPK and NF-kappaB Pathways." Journal of Neuroscience Research, vol. 84, no. 5, 2006, pp. 1037-46.
    Kim YJ, Hwang SY, Oh ES, et al. IL-1beta, an immediate early protein secreted by activated microglia, induces iNOS/NO in C6 astrocytoma cells through p38 MAPK and NF-kappaB pathways. J Neurosci Res. 2006;84(5):1037-46.
    Kim, Y. J., Hwang, S. Y., Oh, E. S., Oh, S., & Han, I. O. (2006). IL-1beta, an immediate early protein secreted by activated microglia, induces iNOS/NO in C6 astrocytoma cells through p38 MAPK and NF-kappaB pathways. Journal of Neuroscience Research, 84(5), pp. 1037-46.
    Kim YJ, et al. IL-1beta, an Immediate Early Protein Secreted By Activated Microglia, Induces iNOS/NO in C6 Astrocytoma Cells Through P38 MAPK and NF-kappaB Pathways. J Neurosci Res. 2006;84(5):1037-46. PubMed PMID: 16881054.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - IL-1beta, an immediate early protein secreted by activated microglia, induces iNOS/NO in C6 astrocytoma cells through p38 MAPK and NF-kappaB pathways. AU - Kim,Yun-Jung, AU - Hwang,So-Young, AU - Oh,Eok-Soo, AU - Oh,Seikwan, AU - Han,Inn-Oc, PY - 2006/8/2/pubmed PY - 2006/12/9/medline PY - 2006/8/2/entrez SP - 1037 EP - 46 JF - Journal of neuroscience research JO - J. Neurosci. Res. VL - 84 IS - 5 N2 - In the present study we sought to examine cell-cell interactions by investigating the effects of factors released by stimulated microglia on inducible nitric oxide (NO) synthase (iNOS) induction in astrocytoma cells. After examining the temporal profiles of proinflammatory molecules induced by lipopolysaccharide (LPS) stimulation in BV2 microglial cells, iNOS and IL-1beta were observed to be the first immediate-response molecules. Removal of LPS after 3 hr stimulation abrogated NO release, whereas a full induction of IL-1beta was retained in BV2 cells. We observed consistently that conditioned medium (CM) from activated microglia resulted in the induction of iNOS in C6 cells, and IL-1beta was shown to be a key regulator of iNOS induction. An IL-1beta-neutralizing antibody diminished NO induction. Incubation with recombinant IL-1beta stimulated NO release to a lesser extent compared to microglial CM; co-treatment of LPS and IL-1beta had a potent, synergistic effect on NO release from C6 cells. Transient transfection with MEK kinase 1 (MEKK1) or nuclear factor-kappa B (NF-kappaB) expression plasmids induced iNOS, and IL-1beta further enhanced the MEKK1 response. Furthermore, IL-1beta-mediated NO release from C6 cells was significantly suppressed by inhibition of p38 mitogen activated protein kinase (MAPK) or NF-kappaB by specific chemical inhibitors. Both IL-1beta and MEKK1 stimulated p38 and JNK MAPKs, as well as the NF-kappaB pathway, to induce iNOS in C6 cells. Microglia may represent an anti-tumor response in the central nervous system, which is potentiated by the local secretion of immunomodulatory factors that in turn affects astrocytoma (glioma) cells. A better understanding of microglia-glioma or microglia-astrocyte interactions will help in the design of novel immune-based therapies for brain tumors or neuronal diseases. SN - 0360-4012 UR - https://www.unboundmedicine.com/medline/citation/16881054/IL_1beta_an_immediate_early_protein_secreted_by_activated_microglia_induces_iNOS/NO_in_C6_astrocytoma_cells_through_p38_MAPK_and_NF_kappaB_pathways_ L2 - https://doi.org/10.1002/jnr.21011 DB - PRIME DP - Unbound Medicine ER -