Search

Pentamidine is an antiprotozoal drug with additional antiinflammatory activities that are not well understood. We now report that pentamidine inhibited the human whole blood production of the chemotactic cytokines (chemokines) interleukin (IL)-8, growth related gene α (GROα) and monocyte chemotactic protein-1 (MCP-1). The title compound dose-dependently suppressed the lipopolysaccharide (LPS)- and phytohemagglutinin (PHA)-stimulated whole blood generation of these chemokines with IC-values of 2.1 and 2.2 μM (IL-8), 2.4 and 1.8 μM (GROα) and 2.8 and 2.4 μM (MCP-1). The inhibition was specific: when tested at 10 μM, pentamidine had no significant inhibitory effect on the PHA-induced generation of the non-chemotactic cytokines tumor necrosis factor-α (TNF-α), IL-1β, IL-2, IL-4, IL-5, IL-10 and interferon-ψ (IFN-ψ), except for a partial inhibition on IL-6. Time course experiments indicated that pentamidine (10 μM) retained its ability to inhibit PHA-stimulated IL-8 production even when its addition was delayed for up to 24 h after mitogen stimulation. Furthermore, reverse transcription PCR studies showed that pentamidine had no effect on IL-8 mRNA expression. These finding indicate that pentamidine is a posttranscription acting inhibitor of human chemokine production. This activity may contribute to the antiinflammatory action ascribed to the title compound. [ABSTRACT FROM AUTHOR]

The ability of dexamethasone and prednisolone (corticosteroids), FK506 and cyclosporin A (T cell immunosuppressants), and of nitraquazone and rolipram (phosphodiesterase IV inhibitors) to inhibit cytokine production by stimulated human blood was investigated. Heparinized human blood obtained from normal healthy volunteers was stimulated with phytohemagglutinin (PHA) in the presence or absence of drug. After different incubation times, supernatant levels of interleukin (IL)-2, IL-5, granulocyte-macrophage colony stimulating factor (GM-CSF) and interferon γ (IFN- γ) were quantified by ELISA. Dexamethasone strongly inhibited the production of IL-5 (IC = 0.004 µM), was less potent against IL-2 and IFN- γ (IC = 0.02-0.05 µM) and showed a relatively weak effect against GM-CSF (IC = 0.6 µM). Similarly prednisolone potently suppressed IL-5 generation (IC=0.05 µM), displayed a more modest activity on IL-2 and IFN- γ (IC = 0.2-0.3 µM) and exerted only partial effects (43% inhibition at 1 µM) on GM-CSF. FK506 strongly suppressed the production of IL-2 (IC = 0.01 µM) and GM-CSF (IC = 0.03 µM), but was inactive (<30% inhibition at 1 µM) against IL-5 and IFN- γ. Similarly, cyclosporin A reduced the generation of IL-2 (IC = 0.4 µM) and GM-CSF (IC = 0.6 µM) while barely affecting the other two cytokines. Nitraquazone and rolipram were most active in reducing the production of IL-5 (IC = 0.8 and 1.3 µM, respectively), while their potency against IL-2, GM-CSF and IFN- γ was 3-6 times lower, with IC's between 2.4 and 8.0 µM. These data indicate that corticosteroids, T cell immunosuppressants and phosphodiesterase IV inhibitors affect cytokine production by PHA-stimulated human blood cells in a differential and 'pharmacotypical' manner. [ABSTRACT FROM AUTHOR]