Abstract
Endothelial cells (ECs) are key players in inflammation and immune responses involved in numerous pathologies. Although attempts were experimentally undertaken to prevent and control EC activation, drug leads and probes still remain necessary. Natural products (NPs) from Clusiaceous and Calophyllaceous plants were previously reported as potential candidates to prevent endothelial dysfunction. The present study aimed to identify more precisely the molecular scaffolds that could limit EC activation. Here, 13 polyphenols belonging to 5 different chemical types of secondary metabolites (i.e., mammea coumarins, a biflavonoid, a pyranochromanone acid, a polyprenylated polycyclic acylphloroglucinol (PPAP) and two xanthones) were tested on resting and cytokine-activated EC cultures. Quantitative and qualitative changes in the expression of both adhesion molecules (VCAM-1, ICAM-1, E-selectin) and major histocompatibility complex (MHC) molecules have been used to measure their pharmaceutical potential. As a result, we identified 3 mammea coumarins that efficiently reduce (up to >90% at 10 μM) both basal and cytokine-regulated levels of MHC class I, class II, MICA and HLA-E on EC surface. They also prevented VCAM-1 induction upon inflammation. From a structural point of view, our results associate the loss of the free prenyl group substituting mammea coumarins with a reduced cellular cytotoxicity but also an abrogation of their anti-inflammatory potential and a reduction of their immunosuppressive effects. A PPAP, guttiferone J, also triggers a strong immunomodulation but restricted to HLA-E and MHC class II molecules. In conclusion, mammea coumarins with a free prenyl group and the PPAP guttiferone J emerge as NPs able to drastically decrease both VCAM-1 and a set of MHC molecules and to potentially reduce the immunogenicity of the endothelium.
Highlights
Located at the interface between blood and tissues, endothelial cells (ECs) lining the vasculature are key cells involved in the control of vascular homeostasis, blood pressure, coagulation, inflammation and leukocyte trafficking [1]
Among thirteen polyphenols tested during this study, mammea coumarins and polyprenylated polycyclic acylphloroglucinols (PPAPs) such as guttiferone J (11), usually isolated from Clusiaceous and Calophyllaceous species, emerged as Natural products (NPs) with a molecular scaffold able to modulate expression of immune as well as inflammation markers on ECs
A major result from this study is the profile of markers inhibited by the mammea coumarins: Coumarins 3, 5/6, and 8 efficiently reduce both basal and cytokine-regulated levels of major histocompatibility complex (MHC) class I and class II, MHC class I related chain A (MICA) and HLA-E on EC surface up to >90% for MHC class II, HLA-E and MICA
Summary
Located at the interface between blood and tissues, endothelial cells (ECs) lining the vasculature are key cells involved in the control of vascular homeostasis, blood pressure, coagulation, inflammation and leukocyte trafficking [1]. ECs express classical major histocompatibility complex (MHC) class I and class II molecules which participate in the activation of immune responses [2, 3]. Activated ECs promote natural killer (NK), CD4+ and CD8+ T cell activation and effector functions via the upregulation of MHC and MHC-like molecules. EC activation may be transient and reversible or sustained during acute inflammation leading to endothelial cell dysfunction. Attempts to prevent and control EC activation and dysfunction can be achieved experimentally by the inhibition of signaling pathway, such as the NF-κB pathway by antioxidant compounds [e.g. pyrrolidine dithiocarbamate (PDTC)] [5, 6] as well as by apoptosis mediator [7] or effector [8] molecules. Identification of new drug leads and targets is still required in the field
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