title: TNF-α-decreased thrombomodulin expression in monocytes is inhibited by propofol through regulation of tristetraprolin and human antigen R activities.
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.
authors: Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taiwan.
authors: Feng-Yen
authors: FY
authors: Lin
authors: Yi-Ting
authors: YT
authors: Tsai
authors: Chung-Yi
authors: CY
authors: Lee
authors: Chih-Yuan
authors: CY
authors: Lin
authors: Yi-Wen
authors: YW
authors: Lin
authors: Chi-Yuan
authors: CY
authors: Li
authors: Chun-Ming
authors: CM
authors: Shih
authors: Chun-Yao
authors: CY
authors: Huang
authors: Nen-Chung
authors: NC
authors: Chang
authors: Jui-Chi
authors: JC
authors: Tsai
authors: Ta-Liang
authors: TL
authors: Chen
authors: Chien-Sung
authors: CS
authors: Tsai