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.

• Authors: 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
• Journal: Neuropharmacology (Neuropharmacology) Vol. 47 Issue 2 Pg. 243-52 (Aug 2004) ISSN: 0028-3908 [Print] England
• PMID: 15223303 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Inflammatory Agents
• Coumarins
• Cyclic AMP Response Element-Binding Protein
• Cytokines
• KL1037
• Lipopolysaccharides
• NF-kappa B
• Nitrites
• Interleukin-10
• Cyclic AMP
• Nitric Oxide Synthase
• Nitric Oxide Synthase Type II
• Nos2 protein, mouse
• Nos2 protein, rat
• Cyclic AMP-Dependent Protein Kinase Type II
• Cyclic AMP-Dependent Protein Kinases
• Dinoprostone

Topics

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