Abstract
Sepsis is a life-threatening, overwhelming immune response to infection with high morbidity and mortality. Inflammatory response and blood clotting are caused by sepsis, which induces serious organ damage and death from shock. As a mechanism of pathogenesis, platelet-activating factor (PAF) induces excessive inflammatory responses and blood clotting. In this study, we demonstrate that a Class A CpG oligodeoxynucleotide (CpG-A1585) strongly induced PAF acetylhydrolase, which generates lyso-PAF. CpG-A1585 rescued mice from acute lethal shock and decreased fibrin deposition, a hallmark of PAF-induced disseminated intravascular coagulation. Furthermore, CpG-A1585 improved endotoxin shock induced by lipopolysaccharide, which comprises the cell wall of Gram-negative bacteria and inhibits inflammatory responses induced by cytokines such as interleukin-6 and tumor necrosis factor-α. These results suggest that CpG-A1585 is a potential therapeutic target to prevent sepsis-related induction of PAF.
Highlights
Toll-like receptors (TLRs) are a family of pattern recognition receptors distinguished by their role of phylaxis
To investigate whether all classes of CpG ODN can induce platelet-activating factor (PAF)-AH, we examined the effect of CpG-A1585, -B1826, and -C2395 on induction of paf-ah2 mRNA expression and PAF acetylhydrolase (PAF-AH) activity in splenocytes in vitro
Since CpG-A1585 containing unmethylated CpG dinucleotides triggers the vertebrate immune response through TLR9 activation [23, 24], we examined whether a CpG motif in CpG-A1585 would affect CpG-A1585-induced paf-ah2 mRNA expression using nonCpG ODN of CpG-A1585
Summary
Toll-like receptors (TLRs) are a family of pattern recognition receptors distinguished by their role of phylaxis. TLRs recognize pathogen-associated molecular patterns (PAMPs) and activate immune signaling through innate and acquired immunity [1,2,3]. TLR4 recognizes lipopolysaccharide (LPS) derived from gram-negative bacteria and induces production of inflammatory cytokines such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, interferon (IFN)-γ, and IL-12 from macrophages and dendritic cells. CpG-A Rescues Mice from Sepsis pathogens recognizing DNA comprising unmethylated CpG motifs present in bacteria and viruses [6]. CpG ODN stimulates a strong innate immunity response, which may be inhibited by suppressive/inhibitory ODN (iODN) [7, 13]. Shirota et al reported that an iODN (A151) protects mice from endotoxin shock. Endotoxin shock worsened by treatment with Class B CpG ODN [5]
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