Ephedrine hydrochloride inhibits PGN-induced inflammatory responses by promoting IL-10 production and decreasing proinflammatory cytokine secretion via the PI3K/Akt/GSK3β pathway

Abstract

Approaches for controlling inflammatory responses and reducing the mortality rate of septic patients remain clinically ineffective; new drugs need to be identified that can induce anti-inflammatory responses. Ephedrine hydrochloride (EH) is a compound that is widely used in cardiovascular diseases, especially to treat hypotension caused by either anesthesia or overdose of antihypertensive drugs. In this study, we reported that EH also plays an important role in the control of the inflammatory response. EH increased IL-10 and decreased proinflammatory cytokine (IL-6, tumor-necrosis factor (TNF)-a, IL-12 and IL-1b) expression in primary peritoneal macrophages and Raw264.7 cells treated with peptidoglycan (PGN), a Gram-positive cell wall component. The anti-inflammatory role of EH was also demonstrated in an experimental mouse model of peritonitis induced by intraperitoneal PGN injection. The phosphatidylinositol 3-kinase (PI3K)/Akt pathway was found to be responsible for the EH-mediated increase in IL-10 production and decrease in IL-6 expression. Therefore, our results illustrated that EH can help maintain immune equilibrium and diminish host damage by balancing the production of pro-and anti-inflammatory cytokines after PGN challenge. EH may be a new potential anti-inflammatory drug that can be useful for treating severe invasive Gram-positive bacterial infection.

Inhibition of Toll-like receptor 9 attenuates sepsis-induced mortality through suppressing excessive inflammatory response

“…Akt is a key negative regulator of inflammatory response [18, 19]. In the present study, we tested whether Akt activation can be altered by CLP-induced sepsis.…”

GSK3: A Kinase Balancing Promotion and Resolution of Inflammation

“…The increase in IL-10 via CREB due to Akt-mediated GSK3β inactivation has also been demonstrated in murine macrophages in response to Francisella tularensis (FT) [163] and in murine and human macrophages in response to Leishmania donovani (LD) infection [164]. Furthermore, increased IL-10 and decreased IL-6 production due to Ser9-dependent GSK3β inactivation has been observed in PGN-treated primary murine peritoneal macrophages and RAW cells following EH application [148]. GSK3β-Ser9 phosphorylation has also been detected in FT-infected murine macrophages [163] and LPS-or LD infection-challenged RAW cells [165].…”

“…Likewise, treatment with LiCl resulted in an amelioration of peritonitis in a murine Pam3CSK4-induced peritonitis model [145]. In mice with peptidoglycan (PGN)-induced peritonitis, anti-inflammatory effects (increased IL-10, decreased TNF, IL-1β, IL-6) could be elicited by ephedrine hydrochloride (EH), a substance that inhibits GSK3β via the PI3K-Akt axis in cell culture experiments [148] (see Section 3.1.3). In a rat model of ischemic stroke, the application of GSK3 inhibitor VIII significantly reduced infarct volume, brain swelling, and neutrophil infiltration as well as signs of apoptosis (caspase-3 activation) and inflammation (COX-2 amounts; number of astrocytes, monocytes, and macrophages) [149].…”

The Antiemetic Effect of Xiao‐Ban‐Xia‐Tang Formula against Cisplatin‐Induced Emesis is Mediated through Inhibition of NLRP3 Inflammasome Activation in a Rat Pica Model

“…6-Gingerol significantly improved the overall complete response (CR) rate in CINV, appetite, and quality of life in cancer patients receiving adjuvant chemotherapy [27]. However, several components of XBXT identified by high-performance liquid chromatography (HPLC) have been demonstrated to have anti-inflammatory effects [28][29][30]. Among them, 6-shogaol has a potent capacity to attenuate canonical NLRP3 inflammasome-mediated IL-1β secretion in THP-1 macrophages [31].…”