ヒト単核球由来サイトカイン産生の薬物による制御に関する研究

抄録

We investigated the effects of drugs, especially anti-pulmonary disease agents, on the production of cytokines from human peripheral blood mononuclear cells (PBMC). Roxithromycin (RXM), a macrolide antibiotic with the structure of 14-member macrocycline ring increased adherent cells (monocyte/macrophages), whereas it suppressed the proliferation of PBMC stimulated with phytohemagglutinin (PHA). RXM suppressed the production of IL-1β and TNF-α from lipopolysaccharide (LPS)-stimulated PBMC in a dose-dependent manner. Levofloxacin, a fluorinated quinolone, increased IL-2 production by PBMC stimulated with PHA. The production of GM-CSF and soluble IL-2 receptor was suppressed at high concentrations of LVFX. LVFX suppressed IL-1β production, but did not the production of TNF-α and IL-8 production. A β-adrenoceptor agonists (β-agonist), procaterol, clenbuterol, fenoterol and terbutaline suppressed the production of TNF- and IL-1β. TNF-α production was almost completely suppressed by dibutyryl cyclic AMP (dbcAMP), whereas IL-1β production appeared to be partially refractory even at the highest concentration examined. Both procaterol and theophylline elevated cAMP levels in LPS-stimulated PMBC, but the effect of procaterol was limited. The inhibition of the production of TNF-α and IL-1β by procaterol was additively potentiated with theophylline. Of examined phosphodiesterase (PDE) isozyme inhibitors type IV PDE inhibitors were more effective in inhibiting the production of TNF-α and IL-1β by LPS-stimulated PBMC than a nonselective, type III or type III/IV inhibitor. The addition of the β-agonist increased the inhibitory effect of tested PDE inhibitors on the production of TNF-α and IL-1β Type IV, type III and nonselective PDE inhibitors were effective in inhibiting the production of IFN-γ and IL-2 in a dose-dependent manner. In contrast, the production of IL-4 and IL-5 was inhibited by only the highest concentration of type IV inhibitor, and other agents had no effect on the production. Similarly, dbcAMP inhibited the production of IFN-γ and IL-2 more potently than that of IL-4 and IL-5. The addition of the β-agonist increased the inhibitory effect of tested PDE inhibitors on the production of IFN-γ and IL-2 production. These findings indicate that these agents have an immunodulatory action on the production of cytokines by PBMC and also indicate that they could be potent pharmacological agents for the treatment of diseases in which several cytokines are important etiological factors.