Sphingosine-1-phosphate
Encyclopedia
Sphingosine-1-phosphate (S1P) is a signaling sphingolipid
. It is also referred to as a bioactive lipid mediator. Sphingolipids at large form a class of lipids characterized by a particular aliphatic aminoalcohol, which is sphingosine.
can be released from ceramide
s, a process catalyzed by the enzyme ceramidase
. Phosphorylation of sphingosine is catalyzed by sphingosine kinase
, an enzyme ubiquitously found in the cytosol and endoplasmatic reticulum of various types of cells. S1P can be dephosphorylated to sphingosine by sphingosine phosphatases and can be irreversibly degraded by an enzyme, Sphingosine phosphate lyase.
(HDL). It is less abundant in tissue fluids. This is referred to as the S1P gradient, which seems to have biological significance in immune cell trafficking.
Originally thought as an intracellular second messenger, it was discovered to be an extracellular ligand for G protein-coupled receptor S1PR1 in 1998. It is now known that S1P receptors are members of the Lysophospholipid receptor
family. There are five described to date. Most of the biological effects of S1P are mediated by signaling through the cell surface receptors.
Although S1P is of importance in the entire human body, it is a major regulator of vascular and immune systems. In addition, it might be relevant in the skin
. In the vascular system, S1P regulates angiogenesis, vascular stability, and permeability. In the immune system, it is now recognized as a major regulator of trafficking of T- and B-cells. S1P interaction with its receptor S1PR1 is needed for the egress of immune cells from the lymphoid organs (such as thymus and lymph nodes) into the lymphatic vessels. Inhibition of S1P receptors was shown to be critical for immunomodulation.
S1P at this physiological concentration stimulates migration and invasion of epithelial ovarian cancer cells but inhibits migration of normal ovarian surface epithelial cells. Most (more than 90%) ovarian cancers are arised from the epithelium of the ovary. Therefore, extracellular S1P could have an important role in cancer progression by promoting migration of epithelial ovarian cancer cells.
The drug fingolimod (FTY720), which agonizes the S1P receptor, prevents autoimmune lymphocytes from moving from the lymphoid organs into the central nervous system. It has been shown in phase III clinical trials to reduce relapses and improve other outcomes in multiple sclerosis.
In addition, S1P modulates the proliferation
of skin cells. This in particular applies to keratinocyte
s while fibroblast
s are not addressed in this way, apart from cell growth and differentiation While S1P suppresses epidermal proliferation as the glucocorticoid
s do, it differs from them in so far, as proliferation of dermal fibroblasts is not reduced. In fact, S1P even activates fibroblast-derived extracellular matrix
protein production. Due to the hyperproliferative action against epidermal cells, S1P has been considered as an active pharmaceutical ingredient for hyperproliferative skin diseases, in particular, psoriasis vulgaris and acne vulgaris.
Although S1P is active at very low concentrations, bioavailability of the compound in human skin is a concern. Therefore, a topical formulation based on specific drug carriers has been considered inevitable.
Sphingolipid
Sphingolipids are a class of lipids containing a backbone of sphingoid bases, a set of aliphatic amino alcohols that includes sphingosine. They were discovered in brain extracts in the 1870s and were named for the mythological Sphinx because of their enigmatic nature. These compounds play...
. It is also referred to as a bioactive lipid mediator. Sphingolipids at large form a class of lipids characterized by a particular aliphatic aminoalcohol, which is sphingosine.
Production
SphingosineSphingosine
Sphingosine is an 18-carbon amino alcohol with an unsaturated hydrocarbon chain, which forms a primary part of sphingolipids, a class of cell membrane lipids that include sphingomyelin, an important phospholipid.-Functions:...
can be released from ceramide
Ceramide
Ceramides are a family of lipid molecules. A ceramide is composed of sphingosine and a fatty acid. Ceramides are found in high concentrations within the cell membrane of cells. They are one of the component lipids that make up sphingomyelin, one of the major lipids in the lipid bilayer...
s, a process catalyzed by the enzyme ceramidase
Ceramidase
Ceramidase is an enzyme which cleaves fatty acids from ceramide, producing sphingosine which in turn is phosphorylated by a sphingosine kinase to form sphingosine-1-phosphate .- Function :...
. Phosphorylation of sphingosine is catalyzed by sphingosine kinase
Sphingosine kinase
Sphingosine kinase is a conserved lipid kinase that catalyzes formation Sphingosine-1-phosphate from the precursor sphingolipid sphingosine. Sphingolipid metabolites, such as ceramide, sphingosine and sphingosine-1-phosphate, are lipid second messengers involved in diverse cellular processes. ...
, an enzyme ubiquitously found in the cytosol and endoplasmatic reticulum of various types of cells. S1P can be dephosphorylated to sphingosine by sphingosine phosphatases and can be irreversibly degraded by an enzyme, Sphingosine phosphate lyase.
Function
S1P is a blood borne lipid mediator, in particular in association with lipoproteins such as high density lipoproteinHigh density lipoprotein
High-density lipoprotein is one of the five major groups of lipoproteins, which, in order of sizes, largest to smallest, are chylomicrons, VLDL, IDL, LDL, and HDL, which enable lipids like cholesterol and triglycerides to be transported within the water-based bloodstream...
(HDL). It is less abundant in tissue fluids. This is referred to as the S1P gradient, which seems to have biological significance in immune cell trafficking.
Originally thought as an intracellular second messenger, it was discovered to be an extracellular ligand for G protein-coupled receptor S1PR1 in 1998. It is now known that S1P receptors are members of the Lysophospholipid receptor
Lysophospholipid receptor
The lysophospholipid receptor group are members of the G protein-coupled receptor family of integral membrane proteins that are important for lipid signaling. In humans, there are eight LPL receptors, each encoded by a separate gene...
family. There are five described to date. Most of the biological effects of S1P are mediated by signaling through the cell surface receptors.
Although S1P is of importance in the entire human body, it is a major regulator of vascular and immune systems. In addition, it might be relevant in the skin
Skin
-Dermis:The dermis is the layer of skin beneath the epidermis that consists of connective tissue and cushions the body from stress and strain. The dermis is tightly connected to the epidermis by a basement membrane. It also harbors many Mechanoreceptors that provide the sense of touch and heat...
. In the vascular system, S1P regulates angiogenesis, vascular stability, and permeability. In the immune system, it is now recognized as a major regulator of trafficking of T- and B-cells. S1P interaction with its receptor S1PR1 is needed for the egress of immune cells from the lymphoid organs (such as thymus and lymph nodes) into the lymphatic vessels. Inhibition of S1P receptors was shown to be critical for immunomodulation.
Clinical significance
The levels of S1P ( in a range of 5-40 µmol/L ) are 5 to 10 times up-regulated in ovarian cancer patients ascites.S1P at this physiological concentration stimulates migration and invasion of epithelial ovarian cancer cells but inhibits migration of normal ovarian surface epithelial cells. Most (more than 90%) ovarian cancers are arised from the epithelium of the ovary. Therefore, extracellular S1P could have an important role in cancer progression by promoting migration of epithelial ovarian cancer cells.
The drug fingolimod (FTY720), which agonizes the S1P receptor, prevents autoimmune lymphocytes from moving from the lymphoid organs into the central nervous system. It has been shown in phase III clinical trials to reduce relapses and improve other outcomes in multiple sclerosis.
In addition, S1P modulates the proliferation
Cell growth
The term cell growth is used in the contexts of cell development and cell division . When used in the context of cell division, it refers to growth of cell populations, where one cell grows and divides to produce two "daughter cells"...
of skin cells. This in particular applies to keratinocyte
Keratinocyte
Keratinocytes are the predominant cell type in the epidermis, the outermost layer of the human skin, constituting 95% of the cells found there. Those keratinocytes found in the basal layer of the skin are sometimes referred to as "basal cells" or "basal keratinocytes"...
s while fibroblast
Fibroblast
A fibroblast is a type of cell that synthesizes the extracellular matrix and collagen, the structural framework for animal tissues, and plays a critical role in wound healing...
s are not addressed in this way, apart from cell growth and differentiation While S1P suppresses epidermal proliferation as the glucocorticoid
Glucocorticoid
Glucocorticoids are a class of steroid hormones that bind to the glucocorticoid receptor , which is present in almost every vertebrate animal cell...
s do, it differs from them in so far, as proliferation of dermal fibroblasts is not reduced. In fact, S1P even activates fibroblast-derived extracellular matrix
Extracellular matrix
In biology, the extracellular matrix is the extracellular part of animal tissue that usually provides structural support to the animal cells in addition to performing various other important functions. The extracellular matrix is the defining feature of connective tissue in animals.Extracellular...
protein production. Due to the hyperproliferative action against epidermal cells, S1P has been considered as an active pharmaceutical ingredient for hyperproliferative skin diseases, in particular, psoriasis vulgaris and acne vulgaris.
Although S1P is active at very low concentrations, bioavailability of the compound in human skin is a concern. Therefore, a topical formulation based on specific drug carriers has been considered inevitable.