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Quercetin disrupts tyrosine-phosphorylated phosphatidylinositol 3-kinase and myeloid differentiation factor-88 association, and inhibits MAPK/AP-1 and IKK/NF-κB-induced inflammatory mediators production in RAW 264.7 cells.
Immunobiology. 2013 Dec; 218(12):1452-67.I

Abstract

Quercetin is a major bioflavonoid widely present in fruits and vegetables. It exhibits anti-inflammatory, anti-tumor, antioxidant properties and reduces cardiovascular disease risks. However, the molecular mechanism of action against inflammation in RAW 264.7 cells is only partially explored. Quercetin effect on LPS-induced gene and protein expressions of inflammatory mediators and cytokines were determined. Moreover, involvement of heme-oxygenase-1, protein kinases, adaptor proteins and transcription factors in molecular mechanism of quercetin action against inflammation were examined. Quercetin inhibited LPS-induced NO, PGE₂, iNOS, COX-2, TNF-α, IL-1β, IL-6 and GM-CSF mRNA and protein expressions while it promoted HO-1 induction in a dose- and time-dependent manner. It also suppressed I-κB-phosphorylation, NF-κB translocation, AP-1 and NF-κB-DNA-binding and reporter gene transcription. Quercetin attenuated p38(MAPK) and JNK1/2 but not ERK1/2 activations and this effect was further confirmed by SB203580 and SP600125-mediated suppressions of HO-1, iNOS, and COX-2 protein expressions. Moreover, quercetin arrested Src, PI3K, PDK1 and Akt activation in a time- and dose-dependent manner, which was comparable to PP2 and LY294002 inhibition of Src, PI3K/Akt and iNOS expressions. Quercetin further arrested Src and Syk tyrosine phosphorylations and their kinase activities followed by inhibition of PI3K tyrosine phosphorylation. Moreover, quercetin disrupted LPS-induced p85 association to TLR4/MyD88 complex and it then limited activation of IRAK1, TRAF6 and TAK1 with a subsequent reduction in p38 and JNK activations, and suppression in IKKα/β-mediated I-κB phosphorylation. Quercetin limits LPS-induced inflammation via inhibition of Src- and Syk-mediated PI3K-(p85) tyrosine phosphorylation and subsequent TLR4/MyD88/PI3K complex formation that limits activation of downstream signaling pathways.

Authors+Show Affiliations

College of Veterinary Medicine, Kyungpook National University, Daegu 702-701, Republic of Korea.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

23735482

Citation

Endale, Mehari, et al. "Quercetin Disrupts Tyrosine-phosphorylated Phosphatidylinositol 3-kinase and Myeloid Differentiation Factor-88 Association, and Inhibits MAPK/AP-1 and IKK/NF-κB-induced Inflammatory Mediators Production in RAW 264.7 Cells." Immunobiology, vol. 218, no. 12, 2013, pp. 1452-67.
Endale M, Park SC, Kim S, et al. Quercetin disrupts tyrosine-phosphorylated phosphatidylinositol 3-kinase and myeloid differentiation factor-88 association, and inhibits MAPK/AP-1 and IKK/NF-κB-induced inflammatory mediators production in RAW 264.7 cells. Immunobiology. 2013;218(12):1452-67.
Endale, M., Park, S. C., Kim, S., Kim, S. H., Yang, Y., Cho, J. Y., & Rhee, M. H. (2013). Quercetin disrupts tyrosine-phosphorylated phosphatidylinositol 3-kinase and myeloid differentiation factor-88 association, and inhibits MAPK/AP-1 and IKK/NF-κB-induced inflammatory mediators production in RAW 264.7 cells. Immunobiology, 218(12), 1452-67. https://doi.org/10.1016/j.imbio.2013.04.019
Endale M, et al. Quercetin Disrupts Tyrosine-phosphorylated Phosphatidylinositol 3-kinase and Myeloid Differentiation Factor-88 Association, and Inhibits MAPK/AP-1 and IKK/NF-κB-induced Inflammatory Mediators Production in RAW 264.7 Cells. Immunobiology. 2013;218(12):1452-67. PubMed PMID: 23735482.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Quercetin disrupts tyrosine-phosphorylated phosphatidylinositol 3-kinase and myeloid differentiation factor-88 association, and inhibits MAPK/AP-1 and IKK/NF-κB-induced inflammatory mediators production in RAW 264.7 cells. AU - Endale,Mehari, AU - Park,Seung-Chun, AU - Kim,Suk, AU - Kim,Seung-Hyung, AU - Yang,Yanyan, AU - Cho,Jae Youl, AU - Rhee,Man Hee, Y1 - 2013/05/09/ PY - 2012/02/19/received PY - 2013/04/28/accepted PY - 2013/6/6/entrez PY - 2013/6/6/pubmed PY - 2014/7/16/medline KW - (4-amino-5-(4-chlorophenyl)-7-(dimethylethyl) pyrazolo [3,4-d]pyrimidine KW - 2-(4-morpholinyl)-8-phenyl-1(4H)-benzopyran-4-1-hydro-chloride KW - AP-1 KW - Adaptor-protein KW - COX-2 KW - ERK1/2 KW - GM-CSF KW - IKK KW - IL-1 receptor-associated kinase 1 KW - IL-1 receptor-associated kinase 4 KW - IL-1β KW - IL-6 KW - IRAK-1 KW - IRAK4 KW - Innate-immunity KW - IκB KW - JNK1/2 KW - LY-294002 KW - MAPK KW - MyD88 KW - NF-κB KW - NO KW - PDK1 KW - PGE(2) KW - PI3K KW - PKB (Akt) KW - PP2 KW - Protein-kinases KW - TAB1 and 2 KW - TAK1 KW - TAK1-binding protein-1 and -2 KW - TNF receptor-associated factor 6 KW - TNF-α KW - TRAF6 KW - Transcription-factor KW - activator protein-1 KW - c-jun N-terminal kinase KW - cyclooxygenase-2 KW - extracellular signal regulated protein kinase KW - granulocyte-macrophage colony stimulating factor KW - iNOS KW - inducible nitric oxide synthase KW - inhibitor of NF-κB KW - inhibitory NF-κB kinase KW - interleukin-1β KW - interleukin-6 KW - mitogen-activated protein kinase KW - myeloid differentiation primary-response protein 88 KW - nitric oxide KW - nuclear factor κB KW - phosphatidylinositol 3-kinase KW - phosphoinositide-dependent protein kinase-1 KW - prostaglandin E(2) KW - protein kinase B KW - transforming-growth-factor-β-activated kinase 1 KW - tumor necrosis factor-α SP - 1452 EP - 67 JF - Immunobiology JO - Immunobiology VL - 218 IS - 12 N2 - Quercetin is a major bioflavonoid widely present in fruits and vegetables. It exhibits anti-inflammatory, anti-tumor, antioxidant properties and reduces cardiovascular disease risks. However, the molecular mechanism of action against inflammation in RAW 264.7 cells is only partially explored. Quercetin effect on LPS-induced gene and protein expressions of inflammatory mediators and cytokines were determined. Moreover, involvement of heme-oxygenase-1, protein kinases, adaptor proteins and transcription factors in molecular mechanism of quercetin action against inflammation were examined. Quercetin inhibited LPS-induced NO, PGE₂, iNOS, COX-2, TNF-α, IL-1β, IL-6 and GM-CSF mRNA and protein expressions while it promoted HO-1 induction in a dose- and time-dependent manner. It also suppressed I-κB-phosphorylation, NF-κB translocation, AP-1 and NF-κB-DNA-binding and reporter gene transcription. Quercetin attenuated p38(MAPK) and JNK1/2 but not ERK1/2 activations and this effect was further confirmed by SB203580 and SP600125-mediated suppressions of HO-1, iNOS, and COX-2 protein expressions. Moreover, quercetin arrested Src, PI3K, PDK1 and Akt activation in a time- and dose-dependent manner, which was comparable to PP2 and LY294002 inhibition of Src, PI3K/Akt and iNOS expressions. Quercetin further arrested Src and Syk tyrosine phosphorylations and their kinase activities followed by inhibition of PI3K tyrosine phosphorylation. Moreover, quercetin disrupted LPS-induced p85 association to TLR4/MyD88 complex and it then limited activation of IRAK1, TRAF6 and TAK1 with a subsequent reduction in p38 and JNK activations, and suppression in IKKα/β-mediated I-κB phosphorylation. Quercetin limits LPS-induced inflammation via inhibition of Src- and Syk-mediated PI3K-(p85) tyrosine phosphorylation and subsequent TLR4/MyD88/PI3K complex formation that limits activation of downstream signaling pathways. SN - 1878-3279 UR - https://www.unboundmedicine.com/medline/citation/23735482/Quercetin_disrupts_tyrosine_phosphorylated_phosphatidylinositol_3_kinase_and_myeloid_differentiation_factor_88_association_and_inhibits_MAPK/AP_1_and_IKK/NF_κB_induced_inflammatory_mediators_production_in_RAW_264_7_cells_ DB - PRIME DP - Unbound Medicine ER -