The immunosuppressive properties of enisoprost and a 5-lipoxygenase inhibitor (SC-45662).
Metabolic derivatives of arachidonic acid such as prostaglandins and leukotrienes may alter immune responses. Enisoprost (ENO), a synthetic prostaglandin E analog, inhibited the response of human peripheral blood mononuclear cells to phytohemagglutinin in a concentration-dependent fashion: .1, 1.0, and 10 micrograms/ml yielding 4.0, 21.7, and 74.3% inhibition, respectively. ENO also potently inhibited both IL-2 production (measured by ELISA) and IL-2 responsiveness (measured by CTLL-2 response to IL-2) in a concentration-dependent manner, yet did not inhibit acquisition of IL-2 receptors. ENO similarly diminished efferent immune function in a concentration-dependent fashion, as measured by inhibition of cytotoxic T cell and natural killer effector function. A 5-lipoxygenase inhibitor (5-LO), SC-45662, also inhibited mononuclear cell response to PHA in a concentration-dependent manner: 0.1, 1.0, and 10 micrograms/ml yielding 5.0, 9.7, and 79.7% inhibition, respectively. Although 5-LO potently inhibited IL-2 production, it had no effect on IL-2 responsiveness or IL-2 receptor acquisition. Like ENO, 5-LO impaired CTL and NK effector function yet was not as potent in inhibiting CTL effector function. In summary, ENO and 5-LO inhibit afferent and efferent immune function. The inhibitory effects of these drugs are not related to cytotoxicity as cell viability is maintained for 72 hr in the presence of these drugs, and the inhibitory effect is reversible when the drugs are removed. The 5-LO does not inhibit mononuclear cell responses simply by shunting the formation of arachidonic acid precursors to form inhibitory prostaglandins, since it does not impair IL-2 responsiveness in a manner similar to ENO. These two compounds may prove to have clinical utility in organ transplantation if safely achieved serum concentrations of these drugs yield in vivo immunosuppression parallel to our in vitro results.
Weir
M R
MR
Department of Medicine, University of Maryland Hospital, Baltimore 21201.
Li
X W
XW
Gomolka
D
D
Peppler
R
R
O'Bryan-Tear
C G
CG
Moran
M A
MA
D000085:Acetates; D000344:Afferent Pathways / Q000187:drug effects; D000527:Alprostadil / Q000031:analogs & derivatives* / Q000494:pharmacology; D000917:Antibody Formation / Q000187:drug effects; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004525:Efferent Pathways / Q000187:drug effects; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007694:Killer Cells, Natural / Q000187:drug effects; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology*; D010636:Phenols; D011459:Prostaglandins E, Synthetic / Q000494:pharmacology*
D000085:Acetates; D007166:Immunosuppressive Agents; D016859:Lipoxygenase Inhibitors; D010636:Phenols; D011459:Prostaglandins E, Synthetic; C066992:(2-((3,5-di-t-butyl-4-hydroxyphenyl)thio)-1-methylpropoxy)acetic acid; D001094:Arachidonate 5-Lipoxygenase; D000527:Alprostadil; C054594:enisoprost