Propofol Inhibits the Activation of p38 through Up-Regulating the Expression of Annexin A1 to Exert Its Anti-Inflammation Effect

Abstract

Inflammatory response is a kind of nonspecific immune response, with the central link of vascular response, which is mainly manifested by changes in neutrophils and vascular endothelial cells. In recent years, the in vivo and in vitro role of intravenous anesthetic propofol in inhibiting inflammatory response has been attracting more and more attention, but the anti-inflammatory mechanisms of propofol for mononuclear cells still remain undefined. In this study, proteomics analysis was applied to investigate protein expression profile changes in serum mononuclear cells following intervention of rats with endotoxemia using propofol. After two-dimensional electrophoresis and mass spectrometric identification, it has been found that the protein Annexin A1 was up-regulated in the propofol intervention group. Annexin A1 is a glucocorticoid-dependent anti-inflammatory protein. After detection using ELISA and Western blot assays, it has also been found that propofol can not only promote the expression of Annexin A1, but also inhibit the phosphorylation level of p38 and release of inflammatory factors (IL-1β, IL-6 and TNF-α) in rats with endotoxemia. In order to further determine the role of up-regulated expression of Annexin A1 in anti-inflammation of propofol, this gene was silenced in vitro in human THP-1 cells, to detect the phosphorylation status of p38 and release of inflammatory factors. The results show that Annexin A1 can negatively regulate phosphorylation of p38 and release of IL-1β, IL-6 and TNF-α in THP-1 cells following propofol intervention and lipopolysaccharide (LPS) stimulation. Our results clearly indicate that propofol can up-regulate Annexin A1 to inhibit the phosphorylation level of p38 and release of IL-1β, IL-6 and TNF-α, so as to inhibit inflammatory response. Therefore, it can be speculated that Annexin A1 might be the key signaling protein in the in vivo and in vitro anti-inflammatory mechanisms of propofol.

Propofol attenuates intermittent hypoxia induced up-regulation of proinflammatory cytokines in microglia through inhibiting the activation of NF-Bκ/p38 MAPK signalling

“…Recently, the anti-inflammatory property of propofol has attracted increasing attention. A wealth of information linking that propofol prohibited inflammatory response through preventing the NF-κB and p38 MAPK signalling and then reducing the release of inflammatory mediators is published [25,26]. In addition, emerging evidence showed that propofol selectively attenuated the activation of NF-κB and p38 MAPK in vascular endothelium during IH exposure [16].…”

“…Moreover, propofol exerted effectively anti-inflammatory properties in human neuroglioma cells treated by sevoflurane through suppressing the NF-κB signalling pathway [26]. An earlier report supported that anti-inflammatory mechanisms of propofol were shown through decreasing the level of phosphorylated p38 MAPK [25]. The anti-inflammatory property of propofol in microglia has become one of the most exciting research topics.…”

“…And it attenuated secretion of proinflammatory cytokines in a hepatocyte nuclear factor-1α-dependent manner [19]. Emerg ing reports suggested that propofol effectively down-regulated inflammatory responses by inhibiting the phosphorylation of nuclear factor-κB (NF-κB) and p38 mitogen-activated protein kinase (MAPK) [25,26,33]. Propofol blocked astrocyte activation upon stimulation with LPS via presenting the NF-κB, p38 MAPK and extracellular signal-regulated protein kinases (ERK) 1/2 pathways [33].…”

Propofol selectively inhibits nuclear factor-κB activity by suppressing p38 mitogen-activated protein kinase signaling in human EA.hy926 endothelial cells during intermittent hypoxia/reoxygenation

“…In addition, propofol exhibits anti-inflammatory properties by decreasing the production of proinflammatory cytokines, altering the production of nitric oxide and inhibiting neutrophil function (13). A study reported that propofol inhibited the activation of p38 MAPK to exert its anti-inflammatory effect (14). However, it remains to be elucidated whether propofol inhibits NF-κB and HIF-1 activity in the vascular endothelial cells during IHR.…”

“…Together, these results indicate that the reduced NF-κB activity caused by propofol acts through the inhibition of the p38 MAPK signaling pathway in HUVECs exposed to IHR. Indeed, propofol has been identified to attenuate the lipopolysaccharide-induced production of proinflammatory cytokines and monocyte chemotactic protein-1 by inhibiting the phosphorylation of p38 MAPK in human THP-1 cells (14).…”