ABSTRACT
The synthetic analogue of phosphatidylserine, cholesterylphosphorylserine (CPHS) inhibits T-cell-mediated immune responses in mice. Tested in cultured mouse spleen cells, CPHS inhibits concanavalin A-induced activation of DNA synthesis (IC50, 3.5 microM). Injected i.p. during the efferent phase, CPHS (25-100 mg/kg) inhibits the manifestations of delayed-type of hypersensitivity. The compound (25 mg/kg i.p., daily) reduces the acute graft-versus-host reaction when given for 5 days to donor mice before the isolation of spleen cells used for the inoculum. These data suggest that the addition of a phosphorylserine group to a steroid ring may produce immunoregulatory compounds.
Subject(s)
Adjuvants, Immunologic/pharmacology , Cholesterol/analogs & derivatives , Cholesterol/pharmacology , Phosphatidylserines/pharmacology , Phosphoserine/analogs & derivatives , T-Lymphocytes/drug effects , Animals , Cholesterol/immunology , Graft vs Host Reaction/drug effects , Hypersensitivity, Delayed/prevention & control , Lymphocyte Activation/drug effects , Male , Mast Cells/drug effects , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Phosphatidylserines/immunology , Phosphoserine/immunology , Phosphoserine/pharmacology , Spleen/cytology , Spleen/drug effectsABSTRACT
Immunoregulation by lipids containing the phosphorylserine (PHS) group has been studied in rodent peritoneal mast cells and human peripheral blood lymphocytes. When PHS is linked to a phospholipid backbone (mono- and diacylglycerol), mast cell activation is produced. However, the effect decreases linking the PHS group to long chain alkanols and is abolished in cholesteryl-PHS, showing that the acylglycerol moiety participates in mast cell activation. Phospholipids containing the PHS group inhibit proliferation of activated peripheral blood lymphocytes. In contrast to mast cells, this effect is retained in alkyl-PHS and is enhanced in cholesteryl-PHS, indicating that in this case the PHS group is the main effector. Among non-phospholipid PHSs, cholesteryl-PHS has been the most interesting since it associates lack of mast cell activation and high inhibitory activity on peripheral blood lymphocytes. This selectivity suggests that this compound may have a potential as an immunosuppressive agent.
Subject(s)
Diglycerides/pharmacology , Glycerides/pharmacology , Lymphocytes/immunology , Lysophospholipids/pharmacology , Mast Cells/immunology , Phosphatidylserines/pharmacology , Animals , Flow Cytometry , Histamine Release , Humans , Lymphocyte Activation/drug effects , Lymphocyte Activation/immunology , Lymphocytes/drug effects , Male , Mast Cells/drug effects , Rats , Rats, Sprague-Dawley , Structure-Activity RelationshipABSTRACT
Absorption and distribution of polyunsaturated fatty acids was investigated in rats receiving lysophospholipids per os (30 mg kg-1). Lysophosphatidylcholine (lysoPC) increased [3H]arachidonate absorption and its incorporation into mucosal phosphatidylcholine. Transport of [3H]arachidonate by the phospholipid fraction of lymph lipoproteins and the level of [3H]arachidonate in plasma and liver lipids was also increased by lyso PC. Lysophosphatidylserine also increased [3H]arachidonate absorption but channeled the fatty acids into the aminophospholipid fraction of mucosal phospholipids, thus decreasing its efflux in lymph lipoproteins. As a consequence, lysophosphatidylserine caused [3H]arachidonate accumulation in mucosa. As similar results were obtained with [14C]linoleate, the data suggest that the addition of an appropriate lysophospholipid to the diet may direct absorption and distribution of polyunsaturated fatty acids.
