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 O. Han, Hua Z. Piao, Keumho Lee, Heesoon Lee, Tong H. Joh, Hee S. Kim

Research output: Contribution to journalArticle

28 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 1
Externally publishedYes

Fingerprint

Microglia
Nitric Oxide Synthase Type II
Anti-Inflammatory Agents
Cytokines
Gene Expression
Interleukin-10
Neurodegenerative Diseases
Up-Regulation
KL1037
Ribonucleases
Neutralizing Antibodies
Interleukin-1
Interleukin-6
Phosphotransferases
Polymerase Chain Reaction

Keywords

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

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Drug Discovery
  • Pharmacology

Cite this

A new anti-inflammatory agent KL-1037 represses proinflammatory cytokine and inducible nitric oxide synthase (iNOS) gene expression in activated microglia. / Kim, Won-Ki; Jang, Pil Geum; Woo, Moon Sook; Han, In O.; Piao, Hua Z.; Lee, Keumho; Lee, Heesoon; Joh, Tong H.; Kim, Hee S.

In: Neuropharmacology, Vol. 47, No. 2, 01.08.2004, p. 243-252.

Research output: Contribution to journalArticle

Kim, Won-Ki ; Jang, Pil Geum ; Woo, Moon Sook ; Han, In O. ; Piao, Hua Z. ; Lee, Keumho ; Lee, Heesoon ; Joh, Tong H. ; Kim, Hee S. / A new anti-inflammatory agent KL-1037 represses proinflammatory cytokine and inducible nitric oxide synthase (iNOS) gene expression in activated microglia. In: Neuropharmacology. 2004 ; Vol. 47, No. 2. pp. 243-252.
@article{5d20f9655b0c4bc280cba5d43929ba83,
title = "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-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.",
keywords = "cAMP, Cytokines, iNOS, KL-1037, Microglia, PKA",
author = "Won-Ki Kim and Jang, {Pil Geum} and Woo, {Moon Sook} and Han, {In O.} and Piao, {Hua Z.} and Keumho Lee and Heesoon Lee and Joh, {Tong H.} and Kim, {Hee S.}",
year = "2004",
month = "8",
day = "1",
doi = "10.1016/j.neuropharm.2004.03.019",
language = "English",
volume = "47",
pages = "243--252",
journal = "Neuropharmacology",
issn = "0028-3908",
publisher = "Elsevier Limited",
number = "2",

}

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 O.

AU - Piao, Hua Z.

AU - Lee, Keumho

AU - Lee, Heesoon

AU - Joh, Tong H.

AU - Kim, Hee S.

PY - 2004/8/1

Y1 - 2004/8/1

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-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.

AB - 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.

KW - cAMP

KW - Cytokines

KW - iNOS

KW - KL-1037

KW - Microglia

KW - PKA

UR - http://www.scopus.com/inward/record.url?scp=3042513502&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=3042513502&partnerID=8YFLogxK

U2 - 10.1016/j.neuropharm.2004.03.019

DO - 10.1016/j.neuropharm.2004.03.019

M3 - Article

VL - 47

SP - 243

EP - 252

JO - Neuropharmacology

JF - Neuropharmacology

SN - 0028-3908

IS - 2

ER -