Abstract
Based on the traditional use and scientific reports on the anti-inflammatory potential of red sandalwood, i.e., the heartwood of Pterocarpus santalinus L., we investigated its activity in a model of IL-1 stimulated endothelial cells. Endothelial cells were stimulated with IL-1 with or without prior incubation with a defined sandalwoodextract (PS), and analyzed for the expression of selected pro-inflammatory genes. The activity of NF-κB, a transcription factor of central importance for inflammatory gene expression was assessed by reporter gene analysis, Western blotting of IκBα, and nuclear translocation studies. In addition, microarray studies were performed followed by verification of selected genes by qPCR and supplemented by bioinformatics analysis. Our results show that PS is able to suppress the induction of E-selectin and VCAM-1, molecules that mediate key steps in the adhesion of leukocytes to the endothelium. It also suppressed the activity of an NF-κB reporter, IκBα phosphorylation and degradation, and the nuclear translocation of NF-κB RelA. In contrast, it stimulated JNK phosphorylation indicating the activation of the JNK signaling pathway. Gene expression profiling revealed that PS inhibits only a specific subset of IL-1 induced genes, while others remain unaffected. Most strongly suppressed genes were the signal transducer TRAF1 and the chemokine CX3CL1, whereas IL-8 was an example of a non-affected gene. Notably, PS also stimulated the expression of certain genes, including ones with negative regulatory function, e.g., members of the NR4A family, the mRNA destabilizing protein TTP as well as the transcription factors ATF3 and BHLHB40. These results provide mechanistic insight into the anti-inflammatory activity of PS, and suggest that it acts through the interplay of negative and positive regulators to achieve a differential inhibition of inflammatory gene expression.
Highlights
Pterocarpus santalinus L. (Fabaceae) grows as a small tree throughout the tropical regions, especially South-East Asia (Arunakumara et al, 2011), and has been used as an ancient Indian as well as traditional Chinese and European remedy (Navada and Vittal, 2014)
Crossing the endothelial monolayer requires endothelial cells (EC) to express, in response to inflammatory stimulation chemokines, cell adhesion molecules, and others to enable and control this process (Mayer et al, 2004). For this reason pro-inflammatory gene expression has proven highly effective as a primary model to monitor pro- and antiinflammatory activities, which are to a large extent regulated by the transcription factor NF-κB
We have analyzed the anti-inflammatory activity of twenty selected herbal extracts using the reduction of the IL-1 stimulated expression of the cell adhesion molecule E-selectin in human umbilical vein endothelial cells (HUVEC) as readout (Lammel et al, 2020)
Summary
Pterocarpus santalinus L. (Fabaceae) grows as a small tree throughout the tropical regions, especially South-East Asia (Arunakumara et al, 2011), and has been used as an ancient Indian as well as traditional Chinese and European remedy (Navada and Vittal, 2014). Inflammation is a common feature of many diseases that can affect almost any tissue and organ; prominent examples include the skin, the gastrointestinal tract, the joints, the liver, and the central nervous and cardiovascular systems (Chen et al, 2018) It involves many different cell types and chemical mediators, one common denominator is that immune cells need to exit from the blood vessels into the underlying tissue to fulfill their function. Crossing the endothelial monolayer requires endothelial cells (EC) to express, in response to inflammatory stimulation chemokines, cell adhesion molecules, and others to enable and control this process (Mayer et al, 2004) For this reason pro-inflammatory gene expression has proven highly effective as a primary model to monitor pro- and antiinflammatory activities, which are to a large extent regulated by the transcription factor NF-κB. A key step in the NF-κB signaling pathway is the phosphorylation and ubiquitination-dependent degradation of its inhibitor IκBα, thereby enabling the cytoplasmic transcription factor to translocate to the nucleus (De Martin et al, 2000; Mussbacher et al, 2019)
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