Abstract
Sphingolipid derivatives play key roles in immune cell migration and function. Synthetic sphingolipid analogues are used as therapeutics to intervene various inflammatory and malignant conditions. We hypothesize that different analogs have different effects on immune cells and therefore can be used as treatment for specific diseases. This study examines the properties of the novel synthetic sphingolipid analog, AD2900, and its effects on immune cell activation and lymphocyte localization in homeostasis. AD2900 is an antagonist for all sphingosine-1-phosphate (S1P) receptors. It demonstrates a significant inhibitory effect on the proliferation of activated human peripheral blood mononuclear cells, which is dependent on cAMP reduction and calcium signal transduction but not on phospholipase C activation. AD2900 causes a significant but reversible downregulation of S1P1 expression on the cell surface. AD2900 administration to C57BL/6J mice leads to the accumulation of T cells in the blood and spleen and in turn reduces T-cell number in the lymph nodes. Moreover, AD2900 treatment shows significant effects on the localization of T-cell subpopulations. These results demonstrate the key roles of S1P in T-cell trafficking in a steady state and suggest a potential clinical application for AD2900. Notably, this sphingolipid analog does not cause a severe lymphopenia. The clinical effect of AD2900 in hemato-oncologic diseases and immune-related diseases needs further investigation.
Highlights
The lysophospholipid, sphingosine-1-phosphate (S1P), is accepted as a major regulator of immune cell trafficking and effector cell function [1, 2]
Previous studies have shown that AD2900 has a higher lethal dose 50% (LD50), which is above 100 mg/kg, and it is stable at room temperature for at least 2 years
To determine whether the effect of inhibition of AD2900 on Peripheral blood mononuclear cells (PBMCs) proliferation is dependent on the same signal transduction pathways, we examined the capacities of the intracellular Ca2+ chelator-BAPTAAM, phosphatidylinositol-specific Phospholipase C (PLC) inhibitor-Et-18OCH3, and cell-permeate exogenous cAMP-8-bromocAMP to alter the suppressive effect of AD2900 and FTY720 on PBMC proliferation
Summary
The lysophospholipid, sphingosine-1-phosphate (S1P), is accepted as a major regulator of immune cell trafficking and effector cell function [1, 2]. S1P naturally exists in a high concentration in the blood and lymph, but its concentrations are of magnitude lower in the tissues, including the thymus, lymph nodes, and interstitial fluids [3, 4]. Immune cells such as lymphocytes, hematopoietic progenitor cells, and dendritic cells employ the S1P gradient to regulate their trafficking [5]. The diverse but selective expression of S1P receptors by different immune cell populations provides lineage-specific regulation of effector functions
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