Abstract
Sphingosine kinase 1(SphK1) a key enzyme that catalyzes the conversion of sphingosine (Sph) to sphingosine 1-phosphate (S1P), so as to maintain the dynamic balance of sphingolipid-rheostat in cells and participate in cell growth and death, proliferation and migration, vasoconstriction and remodeling, inflammation and metabolism. The normal expression of SphK1 maintains the balance of physiological and pathological states, which is reflected in the regulation of inflammatory factor secretion, immune response in traditional immune cells and non-traditional immune cells, and complex signal transduction. However, abnormal SphK1 expression and activity are found in various inflammatory and immune related-diseases, such as hypertension, atherosclerosis, Alzheimer’s disease, inflammatory bowel disease and rheumatoid arthritis. In view of the therapeutic potential of regulating SphK1 and its signal, the current research is aimed at SphK1 inhibitors, such as SphK1 selective inhibitors and dual SphK1/2 inhibitor, and other compounds with inhibitory potency. This review explores the regulatory role of over-expressed SphK1 in inflammatory and immune related-diseases, and investigate the latest progress of SphK1 inhibitors and the improvement of disease or pathological state.
Highlights
Inflammatory immune response is a physiological or excessive response in cells, tissues or organs stimulated by changes in vivo and/or in vitro
Inflammatory immune related-diseases are closely related to inflammatory mediators and inflammatory immune responses caused by immune cells, such as innate immunity involving phagocytes and dendritic cells (DCs), adaptive immunity involving lymphocytes and neutrophils, sphingosine kinase 1 (SphK1) in Inflammatory Immune Related-Diseases and inflammatory responses mediated by various inflammatory mediators
It was found that SphK1 expression and activity are mostly up-regulated in a variety of pathological conditions, and SphK1 and SphK1/sphingosine 1-phosphate (S1P) signal is mainly involved in regulating inflammatory responses and inflammatory mediators
Summary
Inflammatory immune response is a physiological or excessive response in cells, tissues or organs stimulated by changes in vivo and/or in vitro. In addition to immune cells that play a central role in the process of immune response, such as neutrophils, monocytes, macrophages, T and B lymphocytes, there are non-traditional inflammatory cells involved in immune effects, including fibroblasts and endothelial cells They release inflammatory cytokines, such as TNF family, ILs, chemokines and adhesion molecules, which mediate cell activities and regulate inflammation (Gajewski et al, 2013). Matrix metalloproteinase-9 (MMP-9) release from macrophages and neutrophils is thought to play a key role in inflammatory cell migration and cartilage matrix erosion (Yuan et al, 2014), while SphK1 inhibition reduce the release of cytokines and MMP-9 in monocytes and alleviate synovitis These results clearly indicate that the potential of SphK1 inhibition reduces synovial inflammation, and improves immune cell infiltration and angiogenesis. We review SphK1 inhibitors, including selective SphK1 inhibitors, dual SphK1/2 inhibitors and other compounds with inhibitory activity
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