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

Won Ki Kim, Pil Geum Jang, Moon Sook Woo, In Oc Han, Hua Zi Piao, Keumho Lee, Heesoon Lee, Tong H. Joh, Hee Sun Kim

Research output: Contribution to journalArticlepeer-review

30 Citations (Scopus)

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-α, IL-1β and IL-6, while it increased anti-inflammatory IL-10 and TGF-β1 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-κB 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-α 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.

Original languageEnglish
Pages (from-to)243-252
Number of pages10
JournalNeuropharmacology
Volume47
Issue number2
DOIs
Publication statusPublished - 2004 Aug
Externally publishedYes

Keywords

  • Cytokines
  • KL-1037
  • Microglia
  • PKA
  • cAMP
  • iNOS

ASJC Scopus subject areas

  • Pharmacology
  • Cellular and Molecular Neuroscience

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