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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. Sphingosine can be released from ceramides, 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 cleaved by sphingosine phosphatase.
S1P is a blood borne lipid mediator, in particular in association with lipoproteins such as high density lipoprotein (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 EDG-1 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 S1P1 (or EDG-1) is needed for the egress of immune cells from the lymphoiod organs (such as thymus and lymph nodes) into the lymphatic vessels. Inhibition of S1P receptors was shown to be critical for immunomodulation. Currently, an experimental compound, FTY720, is undergoing clinical trials to determine if it is useful in controlling the autoimmune reactions in multiple sclerosis.
In addition, S1P modulates the proliferation of skin cells. This in particular applies to keratinocytes while fibroblasts are not addressed in this way. Apart from cell growth and differentiation While S1P suppresses epidermal proliferation as the glucocorticoids 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.
See also
References
- Lee, MJ et al. (1998). "Sphingosine-1-phosphate as a ligand for the G protein-coupled receptor EDG-1.". Science 279 (5356): 1552-1556. PMID 9488656.
Baumrucker, T et al. (2007). "FTY720, an immunomodulatory sphingolipid mimetic: translation of a novel mechanism into clinical benefit in multiple sclerosis.". Expert Opin Investig Drugs 16 (3): 283-289. PMID 17302523.
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