Abstract
Short-chain fatty acids (e.g., butyrate and propionate) are able to diminish endothelial cell activation. The aim of this study was to investigate whether intracellular IL-33 mediates the effects of butyrate and propionate on TNFα-induced IL-8 production and vascular cell adhesion molecule-1 (VCAM-1) expression. In addition, it was investigated whether regulating NF-κB and MAPK signaling pathways are involved. Intracellular IL-33 was measured in human endothelial cells (HUVECs) pre-incubated for 24 h with butyrate (0.1 mM or 5 mM), propionate (0.3 mM or 10 mM), or trichostatin A (TSA, 0.5 μM) prior to TNFα (1 ng/mL) stimulation (24 h). The effects of butyrate, propionate, and TSA on TNFα-induced IL-8, vascular cell adhesion molecule-1 (VCAM-1), NF-κB, and MAPK signaling pathways in normal HUVECs and IL-33 siRNA (siIL-33)-transfected HUVECs were compared to study the role of IL-33 in the protective effects of butyrate and propionate. Endogenous IL-33 was highly expressed in the perinuclear in HUVECs, which was significantly reduced by TNFα stimulation. The TNFα-induced reduction in IL-33 was prevented by pre-incubation with butyrate or propionate. Butyrate (0.1 mM), propionate (0.3 mM), and TSA inhibited the IL-8 production and activation of NF-κB. Interestingly, this effect was not observed in siIL-33-transfected HUVECs. The effects of butyrate (5 mM), propionate (10 mM), and TSA (0.5 μM) on VCAM-1 expression and activation of MAPK signaling pathways were not affected by siIL-33 transfection. In conclusion, we showed that the inhibitory effects of butyrate and propionate on TNFα-induced IL-8 production were mediated by the HDACs/IL-33/NF-κB pathway, while their effects on VCAM-1 expression might be associated with the HDACs/MAPK signaling pathway, independently of IL-33.
Highlights
Atherosclerosis is a chronic inflammatory disease of the vascular system and causes a significant increase in morbidity and mortality of cardiovascular diseases and is initiated by endothelial cell activation [1,2]
We previously found that the short-chain fatty acids (SCFAs) butyrate and propionate could improve endothelial cell function by reducing the TNFαinduced production of chemokines (IL-8), vascular cell adhesion molecule-1 (VCAM-1)
Accumulating evidence indicates that endothelial activation is an early marker for atherosclerosis [32], which is characterized by increased production of cytokines and Accumulating evidence indicates that endothelial activation is an early marker for atherosclerosis [32], which is characterized by increased production of cytokines and chemokines and the expression of adhesion molecules [3]
Summary
Atherosclerosis is a chronic inflammatory disease of the vascular system and causes a significant increase in morbidity and mortality of cardiovascular diseases and is initiated by endothelial cell activation [1,2]. The molecular signs of cytokine-induced endothelial activation include the upregulated expression of cellular adhesion molecules, cytokines, and chemokines [3]. The risk of developing atherosclerosis is reduced by consuming a diet high in fiber, possibly due to the production of short-chain fatty acids (SCFAs) [4]. We previously found that the SCFAs butyrate and propionate could improve endothelial cell function by reducing the TNFαinduced production of chemokines (IL-8), vascular cell adhesion molecule-1 (VCAM-1). Expression, and peripheral blood mononuclear cell (PBMC) adhesion to endothelial cells via inhibition of histone deacetylases (HDACs) [5,6]. Studies demonstrated that HDACs, especially HDAC3, regulated IL-33 expression in PBMCs [7,8] and epithelial cells [9]
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