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Kaempferol 7-O-β-D-glucoside isolated from the leaves of Cudrania tricuspidata inhibits LPS-induced expression of pro-inflammatory mediators through inactivation of NF-κB, AP-1, and JAK-STAT in RAW 264.7 macrophages.
Chem Biol Interact. 2018 Mar 25; 284:101-111.CB

Abstract

Kaempferol 7-O-β-D-glucoside (KPG), a natural flavonol isolated from Cudrania tricuspidata, has been reported to exert anti-cancer effects; however, its anti-inflammatory effects have not yet been reported. In this study, we demonstrate the suppressive effect of KPG on the production of nitric oxide (NO), prostaglandin E2 (PGE2), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6) in lipopolysaccharide (LPS)-induced RAW 264.7 macrophages and mouse bone marrow-derived macrophages. KPG downregulated the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) at the protein level and iNOS, COX-2, TNF-α, IL-1β, and IL-6 at the mRNA level in LPS-treated RAW 264.7 macrophages. Moreover, we elucidated the underlying molecular mechanism, demonstrating that KPG attenuated LPS-induced nuclear factor-κB (NF-κB) activation by decreasing p65 nuclear translocation, inhibiting κBα (IκBα) phosphorylation/degradation and IκB kinaseα/β (IKKα/β) phosphorylation. KPG additionally reduced LPS-induced activator protein-1 (AP-1) activity by inhibiting c-Fos expression in the nucleus, though c-Jun was not affected. Furthermore, we revealed that KPG significantly abrogated the LPS-induced phosphorylation of signal transducer and activator of transcription (STAT) 1 (Ser 727, Tyr 701) and STAT3 (Tyr 705) through inhibiting the phosphorylation of Janus kinase (JAK) 1 and JAK2, its upstream activating proteins. Taken together, our data suggest that KPG induces anti-inflammatory activity by blocking NF-κB, AP-1, and JAK-STAT signaling pathways in LPS-treated RAW 264.7 macrophages, thus suppressing inflammatory mediators.

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Authors+Show Affiliations

Lee SB
Department of Pharmaceutical Biochemistry, College of Pharmacy, Kyung Hee University, Seoul, Republic of Korea; Department of Life and Nanopharmaceutical Sciences, College of Pharmacy, Kyung Hee University, Seoul 130-701, Republic of Korea.
Shin JS
Department of Pharmaceutical Biochemistry, College of Pharmacy, Kyung Hee University, Seoul, Republic of Korea.
Han HS
Department of Pharmaceutical Biochemistry, College of Pharmacy, Kyung Hee University, Seoul, Republic of Korea; Department of Life and Nanopharmaceutical Sciences, College of Pharmacy, Kyung Hee University, Seoul 130-701, Republic of Korea.
Lee HH
Department of Pharmaceutical Biochemistry, College of Pharmacy, Kyung Hee University, Seoul, Republic of Korea; Department of Life and Nanopharmaceutical Sciences, College of Pharmacy, Kyung Hee University, Seoul 130-701, Republic of Korea.
Park JC
Department of Oriental Medicine Resources, College of Life Science and Natural Resourses, Suncheon National University, Suncheon 57922, Republic of Korea.
Lee KT
Department of Pharmaceutical Biochemistry, College of Pharmacy, Kyung Hee University, Seoul, Republic of Korea; Department of Life and Nanopharmaceutical Sciences, College of Pharmacy, Kyung Hee University, Seoul 130-701, Republic of Korea. Electronic address: ktlee@khu.ac.kr.

MeSH

AnimalsCell SurvivalCyclooxygenase 2Down-RegulationInflammation MediatorsInterleukin-1betaJanus KinasesKaempferolsLipopolysaccharidesMacrophagesMiceMoraceaeNF-kappa BNitric Oxide Synthase Type IIPlant LeavesRAW 264.7 CellsSTAT Transcription FactorsSignal TransductionTranscription Factor AP-1Tumor Necrosis Factor-alpha

Pub Type(s)

Journal Article

Language

eng

PubMed ID

29470957

Citation

Lee, Seung-Bin, et al. "Kaempferol 7-O-β-D-glucoside Isolated From the Leaves of Cudrania Tricuspidata Inhibits LPS-induced Expression of Pro-inflammatory Mediators Through Inactivation of NF-κB, AP-1, and JAK-STAT in RAW 264.7 Macrophages." Chemico-biological Interactions, vol. 284, 2018, pp. 101-111.
Lee SB, Shin JS, Han HS, et al. Kaempferol 7-O-β-D-glucoside isolated from the leaves of Cudrania tricuspidata inhibits LPS-induced expression of pro-inflammatory mediators through inactivation of NF-κB, AP-1, and JAK-STAT in RAW 264.7 macrophages. Chem Biol Interact. 2018;284:101-111.
Lee, S. B., Shin, J. S., Han, H. S., Lee, H. H., Park, J. C., & Lee, K. T. (2018). Kaempferol 7-O-β-D-glucoside isolated from the leaves of Cudrania tricuspidata inhibits LPS-induced expression of pro-inflammatory mediators through inactivation of NF-κB, AP-1, and JAK-STAT in RAW 264.7 macrophages. Chemico-biological Interactions, 284, 101-111. https://doi.org/10.1016/j.cbi.2018.02.022
Lee SB, et al. Kaempferol 7-O-β-D-glucoside Isolated From the Leaves of Cudrania Tricuspidata Inhibits LPS-induced Expression of Pro-inflammatory Mediators Through Inactivation of NF-κB, AP-1, and JAK-STAT in RAW 264.7 Macrophages. Chem Biol Interact. 2018 Mar 25;284:101-111. PubMed PMID: 29470957.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Kaempferol 7-O-β-D-glucoside isolated from the leaves of Cudrania tricuspidata inhibits LPS-induced expression of pro-inflammatory mediators through inactivation of NF-κB, AP-1, and JAK-STAT in RAW 264.7 macrophages. AU - Lee,Seung-Bin, AU - Shin,Ji-Sun, AU - Han,Hee-Soo, AU - Lee,Hwi-Ho, AU - Park,Jong Cheol, AU - Lee,Kyung-Tae, Y1 - 2018/02/20/ PY - 2017/12/19/received PY - 2018/02/02/revised PY - 2018/02/19/accepted PY - 2018/2/23/pubmed PY - 2018/3/28/medline PY - 2018/2/23/entrez KW - AP-1 KW - JAK-STAT KW - Kaempferol 7-O-β-D-glucoside KW - NF-κB KW - RAW 264.7 macrophages SP - 101 EP - 111 JF - Chemico-biological interactions JO - Chem Biol Interact VL - 284 N2 - Kaempferol 7-O-β-D-glucoside (KPG), a natural flavonol isolated from Cudrania tricuspidata, has been reported to exert anti-cancer effects; however, its anti-inflammatory effects have not yet been reported. In this study, we demonstrate the suppressive effect of KPG on the production of nitric oxide (NO), prostaglandin E2 (PGE2), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6) in lipopolysaccharide (LPS)-induced RAW 264.7 macrophages and mouse bone marrow-derived macrophages. KPG downregulated the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) at the protein level and iNOS, COX-2, TNF-α, IL-1β, and IL-6 at the mRNA level in LPS-treated RAW 264.7 macrophages. Moreover, we elucidated the underlying molecular mechanism, demonstrating that KPG attenuated LPS-induced nuclear factor-κB (NF-κB) activation by decreasing p65 nuclear translocation, inhibiting κBα (IκBα) phosphorylation/degradation and IκB kinaseα/β (IKKα/β) phosphorylation. KPG additionally reduced LPS-induced activator protein-1 (AP-1) activity by inhibiting c-Fos expression in the nucleus, though c-Jun was not affected. Furthermore, we revealed that KPG significantly abrogated the LPS-induced phosphorylation of signal transducer and activator of transcription (STAT) 1 (Ser 727, Tyr 701) and STAT3 (Tyr 705) through inhibiting the phosphorylation of Janus kinase (JAK) 1 and JAK2, its upstream activating proteins. Taken together, our data suggest that KPG induces anti-inflammatory activity by blocking NF-κB, AP-1, and JAK-STAT signaling pathways in LPS-treated RAW 264.7 macrophages, thus suppressing inflammatory mediators. SN - 1872-7786 UR - https://www.unboundmedicine.com/medline/citation/29470957/Kaempferol_7_O_β_D_glucoside_isolated_from_the_leaves_of_Cudrania_tricuspidata_inhibits_LPS_induced_expression_of_pro_inflammatory_mediators_through_inactivation_of_NF_κB_AP_1_and_JAK_STAT_in_RAW_264_7_macrophages_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0009-2797(17)31362-5 DB - PRIME DP - Unbound Medicine ER -
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