FJU-C4, a new 2-pyridone compound, attenuates lipopolysaccharide-induced systemic inflammation via p38MAPK and NF-κB in mice
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. H...
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| Veröffentlicht in: | PloS one 2013-12, Vol.8 (12), p.e82877 |
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| creator | Liu, Jung-Sen Jung, Fang Yang, Shih-Hsing Chou, Shang-Shing P Huang, Jhih-Liang Lu, Chang-Lin Huang, Guan-Lin Yang, Pan-Chyr Lin, Jau-Chen Jow, Guey-Mei |
| description | 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. |
| doi_str_mv | 10.1371/journal.pone.0082877 |
| format | Article |
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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.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0082877</identifier><identifier>PMID: 24376600</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Animals ; Anti-inflammatory agents ; Anti-Inflammatory Agents, Non-Steroidal - pharmacology ; Antibiotics ; Cell culture ; Chemical compounds ; Chemical synthesis ; Chemistry ; Cyclooxygenase 2 - genetics ; Cyclooxygenase 2 - metabolism ; Cyclooxygenase-2 ; Cytokines ; Female ; Gene expression ; Gene Expression Regulation ; Inflammation ; Inflammatory diseases ; Inflammatory response ; Interleukin 6 ; Interleukin-1beta - antagonists & inhibitors ; Interleukin-1beta - genetics ; Interleukin-1beta - metabolism ; Interleukin-6 - antagonists & inhibitors ; Interleukin-6 - genetics ; Interleukin-6 - metabolism ; JNK protein ; Kinases ; Lipopolysaccharides ; Macrophages ; MAP Kinase Kinase 4 - genetics ; MAP Kinase Kinase 4 - metabolism ; Mice ; Mice, Inbred BALB C ; Mortality ; mRNA ; NF-kappa B - antagonists & inhibitors ; NF-kappa B - genetics ; NF-kappa B - metabolism ; NF-κB protein ; Nitric oxide ; Nitric Oxide Synthase Type II - genetics ; Nitric Oxide Synthase Type II - metabolism ; Nitric-oxide synthase ; p38 Mitogen-Activated Protein Kinases - genetics ; p38 Mitogen-Activated Protein Kinases - metabolism ; Pharmacology ; Proteins ; Pyridones - pharmacology ; Respiratory therapy ; Rodents ; Sepsis ; Signal Transduction ; Signaling ; Stimulation ; Survival ; Systemic inflammatory response syndrome ; Systemic Inflammatory Response Syndrome - chemically induced ; Systemic Inflammatory Response Syndrome - drug therapy ; Systemic Inflammatory Response Syndrome - genetics ; Systemic Inflammatory Response Syndrome - pathology ; Tumor Necrosis Factor-alpha - antagonists & inhibitors ; Tumor Necrosis Factor-alpha - genetics ; Tumor Necrosis Factor-alpha - metabolism ; Tumor necrosis factor-TNF ; Tumor necrosis factor-α</subject><ispartof>PloS one, 2013-12, Vol.8 (12), p.e82877</ispartof><rights>2013 Liu et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2013 Liu et al 2013 Liu et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c526t-ba0bfcab460d00a90e276fe471e0fd70875a5765ecf268bf4a2d0afcbacc0d323</citedby><cites>FETCH-LOGICAL-c526t-ba0bfcab460d00a90e276fe471e0fd70875a5765ecf268bf4a2d0afcbacc0d323</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3871526/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3871526/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79342,79343</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24376600$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Liu, Jung-Sen</creatorcontrib><creatorcontrib>Jung, Fang</creatorcontrib><creatorcontrib>Yang, Shih-Hsing</creatorcontrib><creatorcontrib>Chou, Shang-Shing P</creatorcontrib><creatorcontrib>Huang, Jhih-Liang</creatorcontrib><creatorcontrib>Lu, Chang-Lin</creatorcontrib><creatorcontrib>Huang, Guan-Lin</creatorcontrib><creatorcontrib>Yang, Pan-Chyr</creatorcontrib><creatorcontrib>Lin, Jau-Chen</creatorcontrib><creatorcontrib>Jow, Guey-Mei</creatorcontrib><title>FJU-C4, a new 2-pyridone compound, attenuates lipopolysaccharide-induced systemic inflammation via p38MAPK and NF-κB in mice</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>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.</description><subject>Animals</subject><subject>Anti-inflammatory agents</subject><subject>Anti-Inflammatory Agents, Non-Steroidal - pharmacology</subject><subject>Antibiotics</subject><subject>Cell culture</subject><subject>Chemical compounds</subject><subject>Chemical synthesis</subject><subject>Chemistry</subject><subject>Cyclooxygenase 2 - genetics</subject><subject>Cyclooxygenase 2 - metabolism</subject><subject>Cyclooxygenase-2</subject><subject>Cytokines</subject><subject>Female</subject><subject>Gene expression</subject><subject>Gene Expression Regulation</subject><subject>Inflammation</subject><subject>Inflammatory diseases</subject><subject>Inflammatory response</subject><subject>Interleukin 6</subject><subject>Interleukin-1beta - antagonists & inhibitors</subject><subject>Interleukin-1beta - genetics</subject><subject>Interleukin-1beta - metabolism</subject><subject>Interleukin-6 - antagonists & inhibitors</subject><subject>Interleukin-6 - genetics</subject><subject>Interleukin-6 - metabolism</subject><subject>JNK protein</subject><subject>Kinases</subject><subject>Lipopolysaccharides</subject><subject>Macrophages</subject><subject>MAP Kinase Kinase 4 - genetics</subject><subject>MAP Kinase Kinase 4 - metabolism</subject><subject>Mice</subject><subject>Mice, Inbred BALB C</subject><subject>Mortality</subject><subject>mRNA</subject><subject>NF-kappa B - antagonists & inhibitors</subject><subject>NF-kappa B - genetics</subject><subject>NF-kappa B - metabolism</subject><subject>NF-κB protein</subject><subject>Nitric oxide</subject><subject>Nitric Oxide Synthase Type II - genetics</subject><subject>Nitric Oxide Synthase Type II - metabolism</subject><subject>Nitric-oxide synthase</subject><subject>p38 Mitogen-Activated Protein Kinases - genetics</subject><subject>p38 Mitogen-Activated Protein Kinases - metabolism</subject><subject>Pharmacology</subject><subject>Proteins</subject><subject>Pyridones - 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Academic</collection><collection>ProQuest Engineering Collection</collection><collection>ProQuest Biological Science Collection</collection><collection>Agricultural Science Database</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biological Science Database</collection><collection>Engineering Database</collection><collection>Nursing & Allied Health Premium</collection><collection>Advanced Technologies & Aerospace Database</collection><collection>ProQuest Advanced Technologies & Aerospace Collection</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Environmental Science Database</collection><collection>Materials Science Collection</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>Engineering Collection</collection><collection>Environmental Science Collection</collection><collection>Genetics Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Liu, Jung-Sen</au><au>Jung, Fang</au><au>Yang, Shih-Hsing</au><au>Chou, Shang-Shing P</au><au>Huang, Jhih-Liang</au><au>Lu, Chang-Lin</au><au>Huang, Guan-Lin</au><au>Yang, Pan-Chyr</au><au>Lin, Jau-Chen</au><au>Jow, Guey-Mei</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>FJU-C4, a new 2-pyridone compound, attenuates lipopolysaccharide-induced systemic inflammation via p38MAPK and NF-κB in mice</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2013-12-23</date><risdate>2013</risdate><volume>8</volume><issue>12</issue><spage>e82877</spage><pages>e82877-</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><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.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>24376600</pmid><doi>10.1371/journal.pone.0082877</doi><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2013-12, Vol.8 (12), p.e82877 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1470558727 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; Free Full-Text Journals in Chemistry; Public Library of Science (PLoS) |
| subjects | Animals Anti-inflammatory agents Anti-Inflammatory Agents, Non-Steroidal - pharmacology Antibiotics Cell culture Chemical compounds Chemical synthesis Chemistry Cyclooxygenase 2 - genetics Cyclooxygenase 2 - metabolism Cyclooxygenase-2 Cytokines Female Gene expression Gene Expression Regulation Inflammation Inflammatory diseases Inflammatory response Interleukin 6 Interleukin-1beta - antagonists & inhibitors Interleukin-1beta - genetics Interleukin-1beta - metabolism Interleukin-6 - antagonists & inhibitors Interleukin-6 - genetics Interleukin-6 - metabolism JNK protein Kinases Lipopolysaccharides Macrophages MAP Kinase Kinase 4 - genetics MAP Kinase Kinase 4 - metabolism Mice Mice, Inbred BALB C Mortality mRNA NF-kappa B - antagonists & inhibitors NF-kappa B - genetics NF-kappa B - metabolism NF-κB protein Nitric oxide Nitric Oxide Synthase Type II - genetics Nitric Oxide Synthase Type II - metabolism Nitric-oxide synthase p38 Mitogen-Activated Protein Kinases - genetics p38 Mitogen-Activated Protein Kinases - metabolism Pharmacology Proteins Pyridones - pharmacology Respiratory therapy Rodents Sepsis Signal Transduction Signaling Stimulation Survival Systemic inflammatory response syndrome Systemic Inflammatory Response Syndrome - chemically induced Systemic Inflammatory Response Syndrome - drug therapy Systemic Inflammatory Response Syndrome - genetics Systemic Inflammatory Response Syndrome - pathology Tumor Necrosis Factor-alpha - antagonists & inhibitors Tumor Necrosis Factor-alpha - genetics Tumor Necrosis Factor-alpha - metabolism Tumor necrosis factor-TNF Tumor necrosis factor-α |
| title | FJU-C4, a new 2-pyridone compound, attenuates lipopolysaccharide-induced systemic inflammation via p38MAPK and NF-κB in mice |
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