title: Geniposide suppresses LPS-induced nitric oxide, PGE2 and inflammatory cytokine by downregulating NF-κB, MAPK and AP-1 signaling pathways in macrophages.
abstract: Inflammatory responses are important to host immune reactions, but uncontrolled inflammatory mediators may aid in the pathogenesis of other inflammatory diseases. Geniposide, an iridoid glycoside found in the herb gardenia, is believed to have broad-spectrum anti-inflammatory effects in murine models but its mechanism of action is unclear. We investigated the action of this compound in murine macrophages stimulated by lipopolysaccharide (LPS), as the stimulation of macrophages by LPS is known to induce inflammatory reactions. We determined the effect of geniposide on LPS-induced production of the inflammatory mediators, nitric oxide (NO) and prostaglandin E2 (PGE2), the mRNA and protein expression of the NO and PGE2 synthases, inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), respectively, and the mRNA and protein expression of the inflammatory cytokine, tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6). Furthermore, nuclear factor (NF)-κB, mitogen-activated protein kinase (MAPK) and activator protein (AP)-1 activity were assayed. To understand the action of geniposide on the NF-κB and MAPK pathways, we studied the effect of NF-κB and MAPK inhibitors on the LPS-induced production of NO, PGE2 and TNF-α. Our findings clearly showed that geniposide mainly exerts its anti-inflammatory effects by inhibiting the LPS-induced NF-κB, MAPK and AP-1 signaling pathways in macrophages, which subsequently reduces overexpression of the inducible enzymes iNOS and COX-2 and suppresses the expression and release of the inflammatory factors, TNF-α, IL-6, NO and PGE2. Thus, geniposide shows promise as a therapeutic agent in inflammatory diseases.
authors.affiliation: Clinical Laboratory Diagnostic Center, Urumqi General Hospital of Lanzhou Military Region, Urumqi 830000, Xinjiang, China. Electronic address: qinghaishi@gmail.com.
authors.forename: Qinghai
authors.initials: Q
authors.lastname: Shi
authors.affiliation: Clinical Laboratory Diagnostic Center, Urumqi General Hospital of Lanzhou Military Region, Urumqi 830000, Xinjiang, China.
authors.forename: Jinjun
authors.initials: J
authors.lastname: Cao
authors.affiliation: Second Section, Lintong Sanatorium of Lanzhou Military Region, Xi'an 710600, Shaanxi, China.
authors.forename: Li
authors.initials: L
authors.lastname: Fang
authors.affiliation: Clinical Laboratory Diagnostic Center, Urumqi General Hospital of Lanzhou Military Region, Urumqi 830000, Xinjiang, China.
authors.forename: Hongyan
authors.initials: H
authors.lastname: Zhao
authors.affiliation: Clinical Laboratory Diagnostic Center, Urumqi General Hospital of Lanzhou Military Region, Urumqi 830000, Xinjiang, China.
authors.forename: Zhengxiang
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Clinical Laboratory Diagnostic Center, Urumqi General Hospital of Lanzhou Military Region, Urumqi 830000, Xinjiang, China.
authors.forename: Jihua
authors.initials: J
authors.lastname: Ran
authors.affiliation: Medical Research Center, Southwestern Hospital, Third Military Medical University, Chongqing 400038, China.
authors.forename: Xinchuan
authors.initials: X
authors.lastname: Zheng
authors.affiliation: Clinical Laboratory Diagnostic Center, Urumqi General Hospital of Lanzhou Military Region, Urumqi 830000, Xinjiang, China.
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Li
authors.affiliation: Clinical Laboratory Diagnostic Center, Urumqi General Hospital of Lanzhou Military Region, Urumqi 830000, Xinjiang, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Clinical Laboratory Diagnostic Center, Urumqi General Hospital of Lanzhou Military Region, Urumqi 830000, Xinjiang, China.
authors.forename: Di
authors.initials: D
authors.lastname: Ge
authors.affiliation: Clinical Laboratory Diagnostic Center, Urumqi General Hospital of Lanzhou Military Region, Urumqi 830000, Xinjiang, China.
authors.forename: Hongming
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Clinical Laboratory Diagnostic Center, Urumqi General Hospital of Lanzhou Military Region, Urumqi 830000, Xinjiang, China.
authors.forename: Li
authors.initials: L
authors.lastname: Wang
authors.affiliation: Clinical Laboratory Diagnostic Center, Urumqi General Hospital of Lanzhou Military Region, Urumqi 830000, Xinjiang, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Ran
authors.affiliation: Clinical Laboratory Diagnostic Center, Urumqi General Hospital of Lanzhou Military Region, Urumqi 830000, Xinjiang, China. Electronic address: dxpjf@163.com.
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Fu
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D002070:Butadienes / Q000494:pharmacology; D002460:Cell Line; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors; D032062:Gardenia; D007093:Imidazoles / Q000494:pharmacology; D018836:Inflammation Mediators / Q000378:metabolism; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D039823:Iridoids / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000276:immunology; D017737:Macrophages, Peritoneal / Q000187:drug effects* / Q000276:immunology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D009570:Nitriles / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D013450:Sulfones / Q000494:pharmacology; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: C434003:3-(4-methylphenylsulfonyl)-2-propenenitrile; D000893:Anti-Inflammatory Agents; D002070:Butadienes; D007093:Imidazoles; D018836:Inflammation Mediators; D015850:Interleukin-6; D039823:Iridoids; D008070:Lipopolysaccharides; D016328:NF-kappa B; D009570:Nitriles; D011725:Pyridines; D013450:Sulfones; D018808:Transcription Factor AP-1; D014409:Tumor Necrosis Factor-alpha; C113580:U 0126; C007835:geniposide; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; D051546:Cyclooxygenase 2; D048049:Extracellular Signal-Regulated MAP Kinases; D015232:Dinoprostone; C093642:SB 203580
keywords: Activator protein (AP)-1; Geniposide; Inflammation; Mitogen-activated protein (MAP) kinases; Nuclear factor (NF)-кB