Ginkgo biloba extract suppresses endotoxin-mediated monocyte activation by inhibiting nitric oxide- and tristetraprolin-mediated toll-like receptor 4 expression

Lee, Yuan-Wen; Lin, Jui-An; Chang, Chuen-Chau; Chen, Yung-Hsiang; Liu, Po-Len; Lee, Ai-Wei; Tsai, Jui-Chi; Li, Chi-Yuan; Tsai, Chien-Sung; Chen, Ta-Liang; Lin, Feng-Yen

doi:10.1016/j.jnutbio.2010.03.002

« Previous Next »The Journal of Nutritional Biochemistry
Volume 22, Issue 4 , Pages 351-359, April 2011

Ginkgo biloba extract suppresses endotoxin-mediated monocyte activation by inhibiting nitric oxide- and tristetraprolin-mediated toll-like receptor 4 expression

Yuan-Wen Lee
- Department of Anesthesiology, Taipei Medical University and Hospital, Taipei 110, Taiwan
Jui-An Lin
- Department of Anesthesiology, Taipei Medical University and Hospital, Taipei 110, Taiwan
Chuen-Chau Chang
- Department of Anesthesiology, Taipei Medical University and Hospital, Taipei 110, Taiwan
Yung-Hsiang Chen
- Graduate Institute of Integrated Medicine, China Medical University, Taichung 404, Taiwan
Po-Len Liu
- Department of Respiratory Therapy, College of Medicine, Kaohsiung Medical, University, Kaohsiung 807, Taiwan
Ai-Wei Lee
- Graduate Institute of Basic Medical Sciences and Department of Anatomy, Taipei Medical University, Taipei 110, Taiwan
Jui-Chi Tsai
- Graduate Institute of Medical Sciences and Division of cardiovascular surgery, National Defense Medical Center, Taipei 114, Taiwan
- Ta-Liang Chen and Jui-Chi Tsai contributed equal to the first author in this work.
Chi-Yuan Li
- Graduate Institute of Clinical Medical Sciences and Department of Anesthesia, China Medical University and Hospital, Taichung 404, Taiwan
- Corresponding author. Department of Anesthesiology, School of Medicine, Taipei Medical University, Taipei, Taiwan.
Chien-Sung Tsai
- Graduate Institute of Medical Sciences and Division of cardiovascular surgery, National Defense Medical Center, Taipei 114, Taiwan
Ta-Liang Chen
- Department of Anesthesiology, Taipei Medical University and Hospital, Taipei 110, Taiwan
- Ta-Liang Chen and Jui-Chi Tsai contributed equal to the first author in this work.
Feng-Yen Lin
- Department of Anesthesiology, Taipei Medical University and Hospital, Taipei 110, Taiwan
- Corresponding author. Department of Anesthesiology, School of Medicine, Taipei Medical University, Taipei, Taiwan.

Received 21 September 2009; received in revised form 19 February 2010; accepted 2 March 2010. published online 26 July 2010.

Abstract

Monocytes expressing toll-like receptor 4 (TLR4) play a major role in regulating the innate immune response and are involved in systemic inflammation. Previous studies have shown that Ginkgo biloba extract (GBE) may act as a therapeutic agent for some cardiovascular and neurological disorders. The objective of this study was to determine whether GBE could modulate immunity in human cells. The monocytic cell line THP-1 was used. Enzyme-linked immunosorbent assay results showed that lipopolysaccharide (LPS) induces the expression of monocyte chemotactic protein-1 (MIP-1), tumor necrosis factor-α, stromal cell-derived factor-1, and MIP-1α, and this induction may be repressed by GBE treatment due to TLR4 blockade. The Griess reagent assay and western blot analysis showed that GBE-mediated inhibition of TLR4 expression was associated with the activation of mitogen-activated protein kinase and production of nitric oxide (NO). Actinomycin D chase experiments demonstrated that GBE decreased the TLR4 mRNA stability in cells. Confocal microscopy and real-time polymerase chain reaction showed that GBE induced the expression of intracellular tristetraprolin (TTP). Transfection with TTP siRNA reversed the effects of GBE in naïve or TLR4-overexpressing cells. Treatment with SNAP (an NO donor) may increase intracellular TTP expression in cells. Immunoprecipitation analysis showed that GBE mediates TTP activation and increases the interaction of TTP with the 3′ untranslated region (UTR) of TLR4 mRNA by regulating NO production. Our findings indicate that GBE could decrease the sensitivity of monocytes to LPS. Utilizing TTP to control TLR4 expression may be a promising approach for controlling systemic inflammation, and GBE may have potential applications in the clinical treatment of immune diseases.

Keywords: Toll-like receptor 4, Ginkgo biloba extract, Tristetraprolin, Nitric oxide