Please use this identifier to cite or link to this item: http://scholarbank.nus.edu.sg/handle/10635/30003
Title: MOLECULAR TARGETS OF RESVERATROL IN LPS-SIGNALING AND THERAPEUTIC EFFECT OF RESVERATROL IN EXPERIMENTAL SEPSIS
Authors: WANG BINBIN
Keywords: inflammation,lipopolysaccharide,signaling,sepsis,resveratrol,autophagy
Issue Date: 5-Aug-2011
Source: WANG BINBIN (2011-08-05). MOLECULAR TARGETS OF RESVERATROL IN LPS-SIGNALING AND THERAPEUTIC EFFECT OF RESVERATROL IN EXPERIMENTAL SEPSIS. ScholarBank@NUS Repository.
Abstract: Inflammation is an important homeostatic host response. By eliciting inflammatory responses, the human immunosurveillance combats invading pathogens. However, severe infection-inflammation response syndrome may result from overactivation of the immune system, which in turn damages the host¿s tissues. Sepsis is a life-threatening disorder that arises from the body¿s excessive responses to infection. It is the leading cause of death and disability for patients in an intensive care unit. Despite vigorous basic research on the molecular mechanisms of sepsis, the patho-physiology of sepsis remains unclear and many clinical trials of sepsis have failed. Therefore, there is still a need for new therapeutic intervention. The natural phytoalexin, resveratrol (RSV), is evident in its anti-inflammatory effects. However, the detailed molecular mechanisms relevant to its anti-inflammatory effects require more investigation. While trying to control the overwhelming inflammation, it is critical not to compromise the host response to clear pathogens. Studies have reported the critical roles of phospholipase D (PLD) and sphingosine kinase (SphK) in controlling inflammatory disease models both in vitro and in vivo. Therefore, we seek to examine the effects of RSV on lipopolysaccharide (LPS) mediated pro-inflammatory responses, and the possible involvement of PLD and SphK in LPS-mediated signaling. We also aim to investigate the therapeutic effects of RSV in a mice model of sepsis. In this study, RSV was shown to exhibit dose-dependent inhibitions of LPS-stimulated inflammatory responses such as cytokines, chemokines and HMGB1 production, and monocyte chemotaxis in human primary monocytes. We next delineate the signaling mechanisms of RSV-modulated, LPS-triggered PLD and SphK activation, ERK phosphorylation and NF-kB activation, which may serve as the molecular basis for the anti-inflammatory effects of RSV. Furthermore, we demonstrate that therapeutic treatment of RSV is protective against polymicrobial sepsis in mice. Mice treated with RSV showed improved survival rate, decreased pro-inflammatory cytokines, chemokines and HMGB1 production, lower local and systemic bacterial load in vivo. These data suggest a potential regimen with RSV which may aid in the clinical treatment of sepsis. Besides its ability to regulate pro-inflammatory signaling pathway triggered by exogenous stimulus such as LPS, RSV also mediates endogenous protein degradation of MyD88, a key adaptor molecule of TLR4. RSV-mediated MyD88 degradation was shown to be autophagy-dependent, which may further contribute to the anti-inflammatory effects of RSV. Interestingly, RSV-induced autophagy was shown to be involved in regulating LPS-triggered SphK activity, suggesting a potential crosstalk between RSV-mediated endogenous autophagic degradation and RSV-modulated exogenous LPS signaling pathway. In summary, this study reports the anti-inflammatory effects of RSV in both endotoxin activation in vitro and polymicrobial sepsis in vivo and provides an in depth molecular basis for its anti-inflammatory properties, thus suggesting the potential therapeutic implication for RSV in treating sepsis.
URI: http://scholarbank.nus.edu.sg/handle/10635/30003
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