Abstract
Background Bupleurum polysaccharides (BPs), isolated from Bupleurum smithii var. parvifolium, possesses immunomodulatory activity, particularly on inflammation. Bacterial endotoxin lipopolysaccharide (LPS) triggers innate immune responses through Toll-like receptor 4 (TLR4) on host cell membrane. The present study was performed to evaluate whether the therapeutic efficacy of BPs on suppression of LPS’s pathogenecity could be associated with the modulating of TLR4 signaling pathway.Methodology/Principal FindingsLPS stimulated expression and activation of factors in the TLR4 signaling system, including TLR4, CD14, IRAK4, TRAF6, NF-κB, and JNK, determined using immunocytochemical and/or Western blot assays. BPs significantly inhibited these effects of LPS. LPS increased pro-inflammatory cytokines (TNF-α, IL-6, IL-1β, IL-12p40, and IFN-β) and NO production, evaluated using ELISA and Griess reaction assays, respectively. BPs antagonized these effects of LPS. Interestingly, BPs alone augmented secretion of some pro-inflammatory cytokines of non-LPS stimulated macrophages and enhanced phagocytic activity towards fluorescent E.coli bioparticles. In a rat model of acute lung injury (ALI) with pulmonary hemorrhage and inflammation, BPs ameliorated lung injuries and suppressed TLR4 expression.SignificanceThe therapeutic properties of BPs in alleviating inflammatory diseases could be attributed to its inhibitory effect on LPS-mediated TLR4 signaling.
Highlights
Lipopolysaccharide (LPS), a major cell wall component of Gram-negative bacteria, is responsible for the overwhelming innate immune response of sepsis syndrome leading to multiple organ failure and death in septic patients [1]
Evaluation of Bupleurum polysaccharides (BPs) cytotoxicity in macrophages Exposure of macrophages to 1-80 μg/ml BPs for 24 h showed no significant increases in cell death (Figure S1), indicating that BPs at the concentrations used in this study were not cytotoxic
Considering tissue macrophages play pivotal roles in the pathogenesis of multiple LPS-induced inflammatory diseases, it is essential that drugs used to ameliorate these diseases should act effectively on macrophages
Summary
Lipopolysaccharide (LPS), a major cell wall component of Gram-negative bacteria, is responsible for the overwhelming innate immune response of sepsis syndrome leading to multiple organ failure and death in septic patients [1]. Various factors and molecular activities are involved in these responses, LPS recognition by the host cells has been considered as a critical step to initiate inflammatory process. TLR4 recruits and activates downstream signaling molecules, including myeloid differentiation primary-response protein 88 (MyD88), IL-1 receptor-associated kinase 4 (IRAK4), and TNF receptorassociated factor 6 (TRAF6) to initiate a cytoplasmic signaling cascade [4]. This signal transduction leads to activation of mitogen-activated protein kinases (MAPKs) [4], phosphorylation and nuclear translocation of transcription factor NF-κB [6], and up-regulation of inflammatory cytokines, and chemokines that precipitate bacterial septic shock [3]. Significance: The therapeutic properties of BPs in alleviating inflammatory diseases could be attributed to its inhibitory effect on LPS-mediated TLR4 signaling
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