TNF-α-decreased thrombomodulin expression in monocytes is inhibited by propofol through regulation of tristetraprolin and human antigen R activities

Feng-Yen Lin, Yi Ting Tsai, Chung Yi Lee, Chih Yuan Lin, Yi Wen Lin, Chi Yuan Li, Chun-Ming Shih, Chun-Yao Huang, Nen-Chung Chang, Jui Chi Tsai, Ta-Liang Chen, Chien Sung Tsai

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

Thrombomodulin (TM) is expressed on the surface of monocytes and is a key regulator of actual immune capacity. Propofol is an anesthetic agent that exerts anti-inflammatory effects. The objective of this study was to determine whether propofol could modulate TM in TNF-α-stimulated monocytes. THP-1 cells and male New Zealand rabbits were used in this study. The results showed that TNF-α decreases the TM expression by mediating posttranscriptional modification, and this inhibition may be repressed by treatment with propofol. Immunofluorescence, immunoprecipitation, and pull-down assays were used to demonstrate that Rac1-dependent nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, Cdc42, and p38 mitogen-activated protein kinase activation, as well as tristetraprolin (TTP) expression, all contributed to the downregulation of TM in TNF-α-treated cells. Propofol reversed the effects of TNF-α on TM downregulation. Propofol mediated the expression of intracellular TTP and the distribution of cytosolic human antigen R (HuR) and changed their interactions with the 3′-untranslated region of TM mRNA regulating by Cdc42 and Rac1. In addition, the animal study showed that propofol regulates TM, TTP, and HuR expression on monocytes in TNF-α-treated rabbits. In conclusion, the inhibition of TM expression in TNF-α-treated monocytes was mediated by the activation of NADPH oxidase and the expression of TTP. Propofol may inhibit the downregulation of TM by mediating NADPH oxidase and TTP inactivation and through the activation of HuR in vitro and in vivo. Utilizing TTP and HuR to control TM expression may be a promising approach for controlling systemic inflammation, and propofol may possess potential implications for the clinical immunity of monocytes after anesthesia or surgery.

Original languageEnglish
Pages (from-to)279-288
Number of pages10
JournalShock
Volume36
Issue number3
DOIs
Publication statusPublished - Sep 2011

    Fingerprint

Keywords

  • Propofol
  • thrombomodulin
  • tristetraprolin

ASJC Scopus subject areas

  • Critical Care and Intensive Care Medicine
  • Emergency Medicine

Cite this