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Effects of Ginkgo biloba extract (EGb 761) and quercetin on lipopolysaccharide-induced signaling pathways involved in the release of tumor necrosis factor-alpha.
Biochem Pharmacol. 2001 Oct 01; 62(7):963-74.BP

Abstract

Administration of bacterial lipopolysaccharide (LPS) to laboratory animals and cultured macrophages induces tumor necrosis factor-alpha (TNF-alpha), a pro-inflammatory cytokine. Pretreatment with Ginkgo biloba extract (EGb 761) inhibited the in vivo production of TNF-alpha (measured by ELISA) after challenge with LPS. To begin to understand the mechanism of this inhibition, we evaluated the in vitro effects of EGb 761 and its flavonoid component, quercetin, on LPS-treated RAW 264.7 macrophages. Pretreatment with EGb 761 or quercetin concentration-dependently inhibited TNF-alpha release, as measured by the L929 fibroblast assay. Northern blotting demonstrated that quercetin inhibited LPS-induced TNF-alpha mRNA, but did not alter its half-life. Activation of mitogen-activated protein kinases (MAPKs) and the redox-sensitive transcription factors, nuclear factor-kappaB (NF-kappaB) and activator protein 1 (AP-1), are key events in the signal transduction pathways mediating TNF-alpha induction. Phosphorylation of extracellular signal-related kinases 1 and 2 (ERK 1/2), p38 MAPK, and Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK), members of the MAPK family, was analyzed by western blotting. Our results suggest that quercetin is unique in its ability to inhibit TNF-alpha transcription by inhibiting the phosphorylation and activation of JNK/SAPK and, therefore, suppressing AP-1-DNA binding [assessed by electrophoretic mobility shift analysis (EMSA)]. Results from western analysis, EMSA, and transient transfections suggest that EGb 761 diminishes LPS-induced NF-kappaB but has no effect on LPS-induced TNF-alpha transcription. Both EGb 761 and quercetin inhibited ERK1/2 phosphorylation and p38 MAPK activity, which are important in the post-transcriptional regulation of TNF-alpha mRNA.

Authors+Show Affiliations

Department of Physiology and Pharmacology, Oregon Health Sciences University, 3181 S.W. Sam Jackson Park Road, Portland, OR 97201-3098, USA.No affiliation info availableNo affiliation info available

Pub Type(s)

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

Language

eng

PubMed ID

11543732

Citation

Wadsworth, T L., et al. "Effects of Ginkgo Biloba Extract (EGb 761) and Quercetin On Lipopolysaccharide-induced Signaling Pathways Involved in the Release of Tumor Necrosis Factor-alpha." Biochemical Pharmacology, vol. 62, no. 7, 2001, pp. 963-74.
Wadsworth TL, McDonald TL, Koop DR. Effects of Ginkgo biloba extract (EGb 761) and quercetin on lipopolysaccharide-induced signaling pathways involved in the release of tumor necrosis factor-alpha. Biochem Pharmacol. 2001;62(7):963-74.
Wadsworth, T. L., McDonald, T. L., & Koop, D. R. (2001). Effects of Ginkgo biloba extract (EGb 761) and quercetin on lipopolysaccharide-induced signaling pathways involved in the release of tumor necrosis factor-alpha. Biochemical Pharmacology, 62(7), 963-74.
Wadsworth TL, McDonald TL, Koop DR. Effects of Ginkgo Biloba Extract (EGb 761) and Quercetin On Lipopolysaccharide-induced Signaling Pathways Involved in the Release of Tumor Necrosis Factor-alpha. Biochem Pharmacol. 2001 Oct 1;62(7):963-74. PubMed PMID: 11543732.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Effects of Ginkgo biloba extract (EGb 761) and quercetin on lipopolysaccharide-induced signaling pathways involved in the release of tumor necrosis factor-alpha. AU - Wadsworth,T L, AU - McDonald,T L, AU - Koop,D R, PY - 2001/9/7/pubmed PY - 2001/9/21/medline PY - 2001/9/7/entrez SP - 963 EP - 74 JF - Biochemical pharmacology JO - Biochem Pharmacol VL - 62 IS - 7 N2 - Administration of bacterial lipopolysaccharide (LPS) to laboratory animals and cultured macrophages induces tumor necrosis factor-alpha (TNF-alpha), a pro-inflammatory cytokine. Pretreatment with Ginkgo biloba extract (EGb 761) inhibited the in vivo production of TNF-alpha (measured by ELISA) after challenge with LPS. To begin to understand the mechanism of this inhibition, we evaluated the in vitro effects of EGb 761 and its flavonoid component, quercetin, on LPS-treated RAW 264.7 macrophages. Pretreatment with EGb 761 or quercetin concentration-dependently inhibited TNF-alpha release, as measured by the L929 fibroblast assay. Northern blotting demonstrated that quercetin inhibited LPS-induced TNF-alpha mRNA, but did not alter its half-life. Activation of mitogen-activated protein kinases (MAPKs) and the redox-sensitive transcription factors, nuclear factor-kappaB (NF-kappaB) and activator protein 1 (AP-1), are key events in the signal transduction pathways mediating TNF-alpha induction. Phosphorylation of extracellular signal-related kinases 1 and 2 (ERK 1/2), p38 MAPK, and Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK), members of the MAPK family, was analyzed by western blotting. Our results suggest that quercetin is unique in its ability to inhibit TNF-alpha transcription by inhibiting the phosphorylation and activation of JNK/SAPK and, therefore, suppressing AP-1-DNA binding [assessed by electrophoretic mobility shift analysis (EMSA)]. Results from western analysis, EMSA, and transient transfections suggest that EGb 761 diminishes LPS-induced NF-kappaB but has no effect on LPS-induced TNF-alpha transcription. Both EGb 761 and quercetin inhibited ERK1/2 phosphorylation and p38 MAPK activity, which are important in the post-transcriptional regulation of TNF-alpha mRNA. SN - 0006-2952 UR - https://www.unboundmedicine.com/medline/citation/11543732/Effects_of_Ginkgo_biloba_extract__EGb_761__and_quercetin_on_lipopolysaccharide_induced_signaling_pathways_involved_in_the_release_of_tumor_necrosis_factor_alpha_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0006-2952(01)00734-1 DB - PRIME DP - Unbound Medicine ER -