Abstract
Despite advances in antibiotic therapy and intensive care, the mortality caused by systemic inflammatory response syndrome and severe sepsis remains high. The use of anti-inflammatory agents to attenuate inflammatory response during acute systemic inflammatory reactions may improve survival rates. Here we show that a newly synthesized 2-pyridone compound (FJU-C4) can suppress the expression of late inflammatory mediators such as iNOS and COX-2 in murine macrophages. The pro-inflammatory cytokines, including TNFα, IL-1β, and IL-6, were dose-dependently suppressed by FJU-C4 both in mRNA and protein levels. In addition, the expression of TNFα was inhibited from as early as 2 hours after exposure to LPS stimulation. The production of mature pro-inflammatory cytokines was also suppressed by pretreatment with FJU-C4 in either cell culture medium or mice serum when stimulated by LPS. FJU-C4 prolongs mouse survival and prevents mouse death from LPS-induced systemic inflammation when the dose of FJU-C4 is over 5 mg/kg. The activities of ERK, JNK, and p38MAPK were induced by LPS stimulation on murine macrophage cell line, but only p38MAPK signaling was dramatically suppressed by pretreatment with the FJU-C4 compound in a dose-dependent manner. NF-κB activation also was suppressed by FJU-C4 compound. These findings suggest that the FJU-C4 compound may act as a promising therapeutic agent against inflammatory diseases by inhibiting the p38MAPK and NF-κB signaling pathway.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
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Cyclooxygenase 2 / genetics
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Cyclooxygenase 2 / metabolism
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Female
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Gene Expression Regulation
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Interleukin-1beta / antagonists & inhibitors
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Interleukin-1beta / genetics
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Interleukin-1beta / metabolism
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Interleukin-6 / antagonists & inhibitors
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Interleukin-6 / genetics
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Interleukin-6 / metabolism
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Lipopolysaccharides
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MAP Kinase Kinase 4 / genetics
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MAP Kinase Kinase 4 / metabolism
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Mice
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Mice, Inbred BALB C
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NF-kappa B / antagonists & inhibitors
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NF-kappa B / genetics*
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NF-kappa B / metabolism
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Nitric Oxide Synthase Type II / genetics
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Nitric Oxide Synthase Type II / metabolism
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Pyridones / pharmacology*
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Signal Transduction
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Systemic Inflammatory Response Syndrome / chemically induced
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Systemic Inflammatory Response Syndrome / drug therapy*
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Systemic Inflammatory Response Syndrome / genetics
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Systemic Inflammatory Response Syndrome / pathology
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Tumor Necrosis Factor-alpha / antagonists & inhibitors
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Tumor Necrosis Factor-alpha / genetics
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Tumor Necrosis Factor-alpha / metabolism
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p38 Mitogen-Activated Protein Kinases / genetics*
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p38 Mitogen-Activated Protein Kinases / metabolism
Substances
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Anti-Inflammatory Agents, Non-Steroidal
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Interleukin-1beta
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Interleukin-6
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Lipopolysaccharides
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NF-kappa B
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Pyridones
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Tumor Necrosis Factor-alpha
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Nitric Oxide Synthase Type II
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Nos2 protein, mouse
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Ptgs2 protein, mouse
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Cyclooxygenase 2
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p38 Mitogen-Activated Protein Kinases
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MAP Kinase Kinase 4
Grants and funding
This research was supported by grant NSC101-2320-B-030-008-MY3 from the National Science Council of Taiwan (
http://web1.nsc.gov.tw/mp.aspx?mp=7) and grant 100CGH-FJU-04 from the Cathay General Hospital (
http://www.cgh.org.tw/en/index.html). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.