It is well known that IL-8 is also regulated by mRNA stability. To provide further evidence for this concept, we performed mRNA stability assays and found that PPAR␦ agonists induce the mRNA stability of IL-8. In addition, we showed that PPAR␦ agonists induce the phosphorylation of ERK1/2 and p38, which are known to be involved in the increase of mRNA stability. The inhibition of these MAPK signaling pathways resulted in a significant suppression of the induced IL-8 expression and the reduced mRNA stability. Therefore, our data provide the first evidence that PPAR␦ induces IL-8 expression in nonstimulated endothelial cells via transcriptional as well as posttranscriptional mechanisms.Peroxisome proliferator-activated receptors (PPARs) 2 are members of the nuclear receptor/ligand-activated transcription factors superfamily and consist of three different subtypes: PPAR␣, PPAR␦, and PPAR␥. The role of these receptors was originally thought to be restricted to lipid and lipoprotein metabolism, glucose homeostasis, and cellular differentiation (1, 2). PPARs are activated by natural ligands, such as eicosanoids and fatty acids. In addition, synthetic antidiabetic thiazolidinediones and lipid-lowering fibrates have been shown to act as activators of PPAR␥ and PPAR␣, respectively (3, 4). To date, PPAR␦, which is expressed in almost all tissues, is the subtype that still remains an interesting target for new pharmaceutical drugs.New evidence suggests that PPAR␦ plays a crucial role in the regulation of differentiation, cell growth, and the metabolism of lipids and glucose (5, 6). With respect to the development of novel drugs, the effects and side effects of PPAR␦ activators are therefore of great importance.In the last few years, knowledge concerning the impact of PPAR␦ in endothelial cell function has increased. showed that the PPAR␦ agonist L-165041 suppresses C-reactive protein-induced IL-6 expression (10). The expression profile of both cytokines during treatment with various PPAR␦ agonist concentrations in the endothelial quiescent status has yet to be analyzed. Nonetheless, these studies showed that PPAR␦ agonists could suppress the inflammatory processes in activated endothelial cells. The impact of PPAR agonists on the normally quiescent endothelium, however, remains to be elucidated. This could be of significant importance due to the possible broad range of applications of PPAR␦ agonists in various diseases, such as chronic inflammation, glucose metabolism, dyslipidemia, obesity, and cancer therapy, to mention only a small number of possible medical applications.During the process of inflammation, proinflammatory cytokines are produced by various cell types. IL-8 is one of these important cytokines. It is secreted at very low levels from noninduced cells, although the secretion is increased rapidly by a * This work was supported by the Wilhelm Sander Stiftung (M. M.).
BackgroundPeroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors that are implicated in the regulation of lipid and glucose homeostasis. PPAR agonists have been shown to control inflammatory processes, in part by inhibiting the expression of distinct proinflammatory genes such as vascular cell adhesion molecule-1 (VCAM-1), IL-8, and intercellular adhesion molecule-1 (ICAM-1). ICAM-1 is an important endothelial membrane receptor that facilitates the transmigration of leukocytes across the endothelium. To date, the influence of PPARα and δ activators on the expression of ICAM-1 in non-induced, quiescent endothelial cells has been unclear. Therefore, we examined the effects of various PPARα and δ agonists on the expression of ICAM-1 in non-stimulated primary human endothelial cells.ResultsWe found that PPARα and PPARδ agonists significantly induced ICAM-1 surface, intracellular protein, and mRNA expression in a time and concentration-dependent manner. The PPARδ induced ICAM-1 expression could be paralleled with a significantly increased T-cell adherence to the endothelial cells whereas PPARα failed to do so. Transcriptional activity studies using an ICAM-1 reporter gene constructs revealed that PPARδ, but not PPARα agonists induced gene expression by stimulating ICAM-1 promoter activity via an Sp1 transcription factor binding site and inhibit the binding of the transcription factors Sp1 and Sp3. Furthermore, we performed mRNA stability assays and found that PPARα and PPARδ agonists increased ICAM-1 mRNA stability.ConclusionTherefore, our data provide the first evidence that PPARα and PPARδ agonists induce ICAM-1 expression in non-stimulated endothelial cells via transcriptional and posttranscriptional mechanisms.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.