Cooperative stimulation of atherogenesis by lipopolysaccharide and palmitic acid-rich high fat diet in low-density lipoprotein receptor-deficient mice.

BACKGROUND AND AIMS: Either lipopolysaccharide (LPS) or high-fat diet (HFD) enriched with saturated fatty acid (SFA) promotes atherosclerosis. In this study, we investigated the effect of LPS in combination with SFA-rich HFD on atherosclerosis and how LPS and SFA interact to stimulate inflammatory response in vascular endothelial cells. METHODS: Low-density lipoprotein receptor-deficient (LDLR-/-) mice were fed a low-fat diet (LFD), HFD with low palmitic acid (PA) (LP-HFD), or HFD with high PA (HP-HFD) for 20 weeks. During the last 12 weeks, half mice received LPS and half received PBS. After treatment, metabolic parameters and aortic atherosclerosis were analyzed. To understand the underlying mechanisms, human aortic endothelial cells (HAECs) were treated with LPS and/or PA and proinflammatory molecule expression was quantified. RESULTS: The metabolic study showed that LPS had no significant effect on cholesterol, triglycerides, free fatty acids, but increased insulin and insulin resistance. Both LP-HFD and HP-HFD increased body weight and cholesterol while LP-HFD increased glucose and HP-HFD increased triglycerides, insulin, and insulin resistance. Analysis of aortic atherosclerosis showed that HP-HFD was more effective than LP-HFD in inducing atherosclerosis and LPS in combination with HP-HFD increased atherosclerosis in the thoracic aorta, a less common site for atherosclerosis, as compared with LPS or HP-HFD. To understand the mechanisms, results showed that LPS and PA synergistically upregulated adhesion molecules and proinflammatory cytokines in HAECs. CONCLUSIONS: LPS and PA-rich HFD cooperatively increased atherogenesis in the thoracic aorta. The synergy between LPS and PA on proinflammatory molecules in HAECs may play an important role in atherogenesis.

Lipopolysaccharide and IL-1ß coordinate a synergy on cytokine production by upregulating MyD88 expression in human gingival fibroblasts.

Both lipopolysaccharide (LPS) and interleukin (IL)-1ß activate the MyD88-dependent signaling pathways to stimulate proinflammatory cytokine expression. However, it remains unknown how LPS and IL-1ß interact with each other to coordinate the stimulation. In this study, we sought to investigate the interaction between LPS and IL-1ß on MyD88-dependent signaling pathways in human gingival fibroblasts (HGFs). Results showed that LPS derived from Porphyromonas gingivalis (Pg LPS) and IL-1ß cooperatively stimulated mitogen-activated protein kinase (MAPK) and nuclear factor kappa B (NFκB) signaling pathways, and subsequent expression of proinflammatory cytokine expression. Furthermore, our results showed that Pg LPS and IL-1ß exerted a synergy on MyD88 expression and knockdown of MyD88 expression by small interfering RNA diminished the synergistic effect of Pg LPS and IL-1ß on IL-6 expression, suggesting that upregulation of MyD88 is involved in the coordinated stimulation by Pg LPS and IL-1ß of proinflammatory cytokine expression. Finally, our results showed that pharmacological inhibitors for MAPK and NFκB significantly reduced IL-6 secretion stimulated by Pg LPS and IL-1ß, indicating that the MyD88-dependent MAPK and NFκB signaling pathways are essential for the upregulation of proinflammatory cytokine expression by Pg LPS and IL-1ß. Taken together, this study showed that LPS and IL-1ß coordinate a synergy on cytokine production by upregulating MyD88 expression in HGFs.