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A new anti-inflammatory agent KL-1037 represses proinflammatory cytokine and inducible nitric oxide synthase (iNOS) gene expression in activated microglia.

Abstract

Excessive proinflammatory cytokine and NO production by activated microglia play a role in neurodegenerative disorders. In this study, we found that a new compound KL-1037 suppressed LPS-induced NO release/inducible nitric oxide synthase expression in BV2 mouse microglial cells. In addition, KL-1037 prominently diminished LPS-induced production of pro-inflammatory cytokines such as TNF-alpha, IL-1 beta and IL-6, while it increased anti-inflammatory IL-10 and TGF-beta 1 production. By RNase protection assay and RT-PCR, we showed that KL-1037 regulated iNOS and cytokines at transcriptional or post-transcriptional level. Further analysis of molecular mechanisms revealed that KL-1037 prominently increased intracellular cAMP levels and potentiated LPS-induced pCREB expression. However, LPS-induced MAP kinase or NF-kappa B activities were slightly or little changed by KL-1037. Treatment with cAMP antagonist or IL-10 neutralizing antibody completely reversed upregulation of IL-10 and partially repression of TNF-alpha or NO induced by KL-1037. These data suggest that microglial inactivation by KL-1037 is at least in part due to activation of PKA pathway and/or upregulation of IL-10. Thus, repressing proinflammatory cytokines and iNOS gene expression in activated microglia by KL-1037 may provide potential therapeutic strategies for various neurodegenerative diseases including ischemic cerebral disease.

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  • Authors+Show Affiliations

    ,

    Department of Pharmacology, Ewha Institute of Neuroscience and Medical Research Center, Ewha Womans University School of Medicine, Seoul, South Korea.

    , , , , , , ,

    Source

    Neuropharmacology 47:2 2004 Aug pg 243-52

    MeSH

    Animals
    Anti-Inflammatory Agents
    Blotting, Western
    Cell Line
    Cell Nucleus
    Cell Survival
    Coumarins
    Cyclic AMP
    Cyclic AMP Response Element-Binding Protein
    Cyclic AMP-Dependent Protein Kinase Type II
    Cyclic AMP-Dependent Protein Kinases
    Cytokines
    Depression, Chemical
    Dinoprostone
    Electrophoretic Mobility Shift Assay
    Enzyme-Linked Immunosorbent Assay
    Gene Expression
    Interleukin-10
    Lipopolysaccharides
    Mice
    Microglia
    NF-kappa B
    Nitric Oxide Synthase
    Nitric Oxide Synthase Type II
    Nitrites
    Nuclease Protection Assays
    Rats
    Reverse Transcriptase Polymerase Chain Reaction

    Pub Type(s)

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

    Language

    eng

    PubMed ID

    15223303

    Citation

    Kim, Won-Ki, et al. "A New Anti-inflammatory Agent KL-1037 Represses Proinflammatory Cytokine and Inducible Nitric Oxide Synthase (iNOS) Gene Expression in Activated Microglia." Neuropharmacology, vol. 47, no. 2, 2004, pp. 243-52.
    Kim WK, Jang PG, Woo MS, et al. A new anti-inflammatory agent KL-1037 represses proinflammatory cytokine and inducible nitric oxide synthase (iNOS) gene expression in activated microglia. Neuropharmacology. 2004;47(2):243-52.
    Kim, W. K., Jang, P. G., Woo, M. S., Han, I. O., Piao, H. Z., Lee, K., ... Kim, H. S. (2004). A new anti-inflammatory agent KL-1037 represses proinflammatory cytokine and inducible nitric oxide synthase (iNOS) gene expression in activated microglia. Neuropharmacology, 47(2), pp. 243-52.
    Kim WK, et al. A New Anti-inflammatory Agent KL-1037 Represses Proinflammatory Cytokine and Inducible Nitric Oxide Synthase (iNOS) Gene Expression in Activated Microglia. Neuropharmacology. 2004;47(2):243-52. PubMed PMID: 15223303.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - A new anti-inflammatory agent KL-1037 represses proinflammatory cytokine and inducible nitric oxide synthase (iNOS) gene expression in activated microglia. AU - Kim,Won-Ki, AU - Jang,Pil-Geum, AU - Woo,Moon-Sook, AU - Han,In-Oc, AU - Piao,Hua Zi, AU - Lee,Keumho, AU - Lee,Heesoon, AU - Joh,Tong H, AU - Kim,Hee-Sun, PY - 2003/09/26/received PY - 2004/02/27/revised PY - 2004/03/29/accepted PY - 2004/6/30/pubmed PY - 2004/9/29/medline PY - 2004/6/30/entrez SP - 243 EP - 52 JF - Neuropharmacology JO - Neuropharmacology VL - 47 IS - 2 N2 - Excessive proinflammatory cytokine and NO production by activated microglia play a role in neurodegenerative disorders. In this study, we found that a new compound KL-1037 suppressed LPS-induced NO release/inducible nitric oxide synthase expression in BV2 mouse microglial cells. In addition, KL-1037 prominently diminished LPS-induced production of pro-inflammatory cytokines such as TNF-alpha, IL-1 beta and IL-6, while it increased anti-inflammatory IL-10 and TGF-beta 1 production. By RNase protection assay and RT-PCR, we showed that KL-1037 regulated iNOS and cytokines at transcriptional or post-transcriptional level. Further analysis of molecular mechanisms revealed that KL-1037 prominently increased intracellular cAMP levels and potentiated LPS-induced pCREB expression. However, LPS-induced MAP kinase or NF-kappa B activities were slightly or little changed by KL-1037. Treatment with cAMP antagonist or IL-10 neutralizing antibody completely reversed upregulation of IL-10 and partially repression of TNF-alpha or NO induced by KL-1037. These data suggest that microglial inactivation by KL-1037 is at least in part due to activation of PKA pathway and/or upregulation of IL-10. Thus, repressing proinflammatory cytokines and iNOS gene expression in activated microglia by KL-1037 may provide potential therapeutic strategies for various neurodegenerative diseases including ischemic cerebral disease. SN - 0028-3908 UR - https://www.unboundmedicine.com/medline/citation/15223303/A_new_anti_inflammatory_agent_KL_1037_represses_proinflammatory_cytokine_and_inducible_nitric_oxide_synthase__iNOS__gene_expression_in_activated_microglia_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0028390804000942 DB - PRIME DP - Unbound Medicine ER -