ABSTRACT
The effect of ST 899, a novel platelet-activating factor (PAF) receptor antagonist, on serum tumor necrosis factor (TNF), interleukin-6 (IL-6), and interferon-gamma (IFN-gamma) production as well as on lethality in an experimental endotoxin shock model was investigated in C57BL/6 mice. In this model, animals receiving 40 mg/kg lipopolysaccharide (LPS) (Escherichia coli 055:B5) intraperitoneally were pretreated with ST 899 administered according to two different schedules. ST 899 pretreatment dose dependently reduced the mortality induced by LPS injection. The PAF receptor antagonist was also able to reduce significantly the LPS-induced increase in serum TNF. Although serum IL-6 levels were not affected, we found that ST 899, when administered intraperitoneally 60 min and intravenously 10 min prior to LPS challenge, had a tendency (at higher doses) to decrease circulating IFN-gamma levels. It is suggested that ST 899 may be beneficial, in combination with current therapies, in the treatment of diseases that involve overproduction of PAF, TNF, and IFN-gamma such as septic shock.
Subject(s)
Platelet Membrane Glycoproteins/antagonists & inhibitors , Receptors, Cell Surface , Receptors, G-Protein-Coupled , Shock, Septic/drug therapy , Animals , Biological Assay , Butyrates , Enzyme-Linked Immunosorbent Assay , Escherichia coli , Interferon-gamma/biosynthesis , Interferon-gamma/blood , Interleukin-6/biosynthesis , Interleukin-6/blood , Lipopolysaccharides/toxicity , Male , Mice , Mice, Inbred C57BL , Platelet Activating Factor/antagonists & inhibitors , Quaternary Ammonium Compounds , Shock, Septic/blood , Shock, Septic/immunology , Time Factors , Tumor Necrosis Factor-alpha/analysis , Tumor Necrosis Factor-alpha/biosynthesisABSTRACT
ST 789 is a new synthetic compound characterized by an amino acidic group joined to the N9 position of the hypoxanthine ring, which has been shown recently to have immunomodulating properties and minimal toxicity. The drug has been reported to protect immunosuppressed mice from microbial infections and tumour growth, and to restore the mitogen-induced proliferation of splenocytes from immunosuppressed young mice. In this study, we show that in vitro addition of ST 789 is able to markedly augment the sheep red blood cells (SRBC) phagocytosis by PEC, and to potentiate the cytotoxic activity of peritoneal exudate (PE) macrophages (M phi) vs the L-M tumour cell line. We also found that ST 789 enhanced the rIFN-gamma-induced NO2- release from cultured PE M phi. Similarly, in vitro addition of ST 789 to the latter cultures significantly increased the production of interleukin 1 (IL-1) and tumour necrosis factor (TNF) induced by lipopolysaccharide (LPS). These studies demonstrate that ST 789 is a potent phagocyte activator for the induction of cytokine release, phagocytosis and cytotoxic activity against tumour cells in vitro.
