Abstract
BackgroundSepsis is a life-threatening organ dysfunction caused by dysregulated host response to infection, and is primarily characterized by an uncontrolled systemic inflammatory response. In the present study, we developed an effective adjunct therapy mediated by a novel mechanism, to attenuate overt inflammation. LPS-treated macrophages were adopted as an in vitro model of endotoxin-induced inflammation during sepsis. Experiments were carried out using primary mouse peritoneal macrophages and the murine macrophage cell line RAW264.7, to elucidate the mechanisms by which HDAC2 modulates endotoxin-induced inflammation.ResultsResults revealed that PAI-1, TNF, and MIP-2 expression were inhibited by theophylline, an HDAC2 enhancer, in a RAW macrophage cell line, following LPS-induced inflammation. Thus, HDAC2 plays an important role in immune defense by regulating the expression of inflammatory genes via the c-Jun/PAI-1 pathway. During LPS-induced inflammation, overexpression of HDAC2 was found to inhibit PAI-1, TNF, and MIP-2 expression. Following LPS stimulation, HDAC2 knockdown increased nuclear translocation and DNA binding of c-Jun to the PAI-1 gene promoter, thereby activating PAI-1 gene transcription. Furthermore, inhibition of PAI-1 by TM5275 alone or in combination with theophylline notably suppressed TNF and MIP-2 expression.ConclusionHDAC2 can attenuate lipopolysaccharide-induced inflammation by regulating c-Jun and PAI-1 expression in macrophages.
Highlights
Sepsis is a life-threatening organ dysfunction caused by dysregulated host response to infection, and is primarily characterized by an uncontrolled systemic inflammatory response
We investigated whether Histone deacetylase 2 (HDAC2) can regulate LPS-induced TNF and MIP-2 expression via the epigenetic regulation of Plasminogen activator inhibitor (PAI)-1
In fig. 2, we found that up-regulation of urokinase plasminogen activator (uPA) secretion was associated with the LPS-induced suppression of TNF, plasminogen activator inhibitor-1 (PAI-1) and MIP-2. uPA is under the tight control of its inhibitor, PAI-1 [44]
Summary
Sepsis is a life-threatening organ dysfunction caused by dysregulated host response to infection, and is primarily characterized by an uncontrolled systemic inflammatory response. We developed an effective adjunct therapy mediated by a novel mechanism, to attenuate overt inflammation. LPS-treated macrophages were adopted as an in vitro model of endotoxin-induced inflammation during sepsis. Sepsis is a life-threatening organ dysfunction that is caused by a dysregulated host response to infection [1]. It is primarily characterized by uncontrolled systemic inflammatory response. Our initial data revealed that histone deacetylase modulators can attenuate endotoxin-induced acute lung injury and inflammation in vitro [10]
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