Abstract
BackgroundSepsis is a complex syndrome characterized by a dysregulated inflammatory response to systemic infection and leads to shock, multiple organ failure and death especially if not recognized early and treated promptly. Previous studies have suggested Maresin 1 (MAR1) can alleviate systemic inflammation in sepsis, but its mechanism has not been clarified.MethodsRAW 264.7 cells and human primary peripheral blood mononuclear cells (hPBMCs) were pretreated with LPS and MAR1. The mRNA expression and supernatant levels of pro-inflammatory cytokines, tumor necrosis factor (TNF-α), interleukin (IL)-1β and IL-6 were evaluated by RT-qPCR and ELISA, respectively. The expression levels of Sirtuin 1 (SIRT1), peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), and Peroxisome proliferator-activated receptor gamma (PPAR-γ) were determined by RT-qPCR and Western blot analysis, respectively.ResultsOur results show that LPS-induced inflammation increased the expression and secretion of proinflammatory cytokines TNF-α, IL-1β and IL-6 and induced suppression of SIRT1, PGC-1α, and PPAR-γ expression, which could be reversed by MAR1. And the effect of MAR1 was eliminated by repression of SIRT1/PPAR-γ and enhanced by PGC-1α overexpression.ConclusionsMAR1 suppressed inflammatory response in LPS-induced RAW 264.7 macrophages and hPBMCs via the SIRT1/PGC-1α/PPAR-γ pathway.
Highlights
Sepsis, defined as a syndrome of systemic inflammatory response (SIRS) caused by infection as a result of an infective process, is a rapidly progressive and lifethreatening syndrome
The results showed that LPS increased secretion of TNF-α, IL-6 and IL-1β in both RAW264.7 cells and human primary peripheral blood mononuclear cells (hPBMCs), which can be reversed by Maresin 1 (MAR1) in a dose-dependent manner (Fig. 1b)
We performed Western blot assay to evaluate the levels of Sirtuin 1 (SIRT1), PGC-1α and PPAR-γ protein, and the results showed that the expression of SIRT1, PGC-1α and PPAR-γ protein were significantly down-regulated in both RAW264.7 cells and hPBMCs caused by LPS (p < 0.001) (Fig. 1c) and upregulated by MAR1 in a dose-dependent manner
Summary
Sepsis, defined as a syndrome of systemic inflammatory response (SIRS) caused by infection as a result of an infective process, is a rapidly progressive and lifethreatening syndrome. Inflammation response can be activated in both macrophages and monocytes, and the inflammatory factors released by macrophages may accelerate the sepsis-induced cell and tissue injury [3, 4]. Lipopolysaccharide (LPS), a component of the outer membrane of Gram-negative bacteria, interacts with specific receptors on host effector cells and induces the release of proinflammatory cytokines [5]. Excessive production of these cytokines can lead to an uncontrolled inflammatory response [6]. Sepsis is a complex syndrome characterized by a dysregulated inflammatory response to systemic infection and leads to shock, multiple organ failure and death especially if not recognized early and treated promptly. Previous studies have suggested Maresin 1 (MAR1) can alleviate systemic inflammation in sepsis, but its mechanism has not been clarified
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