LPS and palmitate synergistically stimulate sphingosine kinase 1 and increase sphingosine 1 phosphate in RAW264.7 macrophages

It has been well established that patients with diabetes or metabolic syndrome (MetS) have increased prevalence and severity of periodontitis, an oral infection initiated by bacteria and characterized by tissue inflammation and destruction. To understand the underlying mechanisms, we have shown that...

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Published in:Journal of leukocyte biology 2018-10, Vol.104 (4), p.843-853
Main Authors: Jin, Junfei, Lu, Zhongyang, Li, Yanchun, Ru, Ji Hyun, Lopes‐Virella, Maria F., Huang, Yan
Format: Article
Language:English
Subjects:
Animals
Apoptosis
ceramide
Ceramides - metabolism
Cytokines - biosynthesis
Drug Synergism
Enzyme Activation - drug effects
fatty acid
Gene Expression Regulation - drug effects
Inflammation
Interleukin-6 - biosynthesis
lipopolysaccharide
Lipopolysaccharides - pharmacology
Lysophospholipids - biosynthesis
Macrophages - drug effects
Macrophages - enzymology
Mice
Palmitates - pharmacology
Phosphotransferases (Alcohol Group Acceptor) - antagonists & inhibitors
Phosphotransferases (Alcohol Group Acceptor) - metabolism
RAW 264.7 Cells
Receptors, Lysosphingolipid - antagonists & inhibitors
RNA Interference
Sphingosine - analogs & derivatives
Sphingosine - biosynthesis
sphingosine 1 phosphate
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Summary:It has been well established that patients with diabetes or metabolic syndrome (MetS) have increased prevalence and severity of periodontitis, an oral infection initiated by bacteria and characterized by tissue inflammation and destruction. To understand the underlying mechanisms, we have shown that saturated fatty acid (SFA), which is increased in patients with type 2 diabetes or MetS, and LPS, an important pathogenic factor for periodontitis, synergistically stimulate expression of proinflammatory cytokines in macrophages by increasing ceramide production. However, the mechanisms by which increased ceramide enhances proinflammatory cytokine expression have not been well understood. Since sphingosine 1 phosphate (S1P) is a metabolite of ceramide and a bioactive lipid, we tested our hypothesis that stimulation of ceramide production by LPS and SFA facilitates S1P production, which contributes to proinflammatory cytokine expression. Results showed that LPS and palmitate, a major SFA, synergistically increased not only ceramide, but also S1P, and stimulated sphingosine kinase (SK) expression and membrane translocation in RAW264.7 macrophages. Results also showed that SK inhibition attenuated the stimulatory effect of LPS and palmitate on IL‐6 secretion. Moreover, results showed that S1P enhanced the stimulatory effect of LPS and palmitate on IL‐6 secretion. Finally, results showed that targeting S1P receptors using either S1P receptor antagonists or small interfering RNA attenuated IL‐6 upregulation by LPS and palmitate. Taken together, this study demonstrated that LPS and palmitate synergistically stimulated S1P production and S1P in turn contributed to the upregulation of proinflammatory cytokine expression in macrophages by LPS and palmitate. LPS and palmitate synergistically increase S1P and, in turn, S1P contributes to upregulation of proinflammatory genes by LPS and palmitate.
ISSN:0741-5400
1938-3673
DOI:10.1002/JLB.3A0517-188RRR