Yoshimura T
Department of Pharmacy, Ogaki Municipal Hospital, 4-86 Minaminokawa-cho, Ogaki 503-8502, Japan.
Yakugaku Zasshi. 2000 Dec;120(12):1277-90. doi: 10.1248/yakushi1947.120.12_1277.
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-1 beta and TNF-alpha 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-1 beta production, but did not the production of TNF-alpha and IL-8 production. A beta-adrenoceptor agonists (beta-agonist), procaterol, clenbuterol, fenoterol and terbutaline suppressed the production of TNF- and IL-1 beta. TNF-alpha production was almost completely suppressed by dibutyryl cyclic AMP (dbcAMP), whereas IL-1 beta production appeared to be partially refractory even at the highest concentration examined. Both procaterol and theophylline elevated cAMP levels in LPS-stimulated PBMC, but the effect of procaterol was limited. The inhibition of the production of TNF-alpha and IL-1 beta 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-alpha and IL-1 beta by LPS-stimulated PBMC than a nonselective, type III or type III/IV inhibitor. The addition of the beta-agonist increased the inhibitory effect of tested PDE inhibitors on the production of TNF-alpha and IL-1 beta Type IV, type III and nonselective PDE inhibitors were effective in inhibiting the production of IFN-gamma 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-gamma and IL-2 more potently than that of IL-4 and IL-5. The addition of the beta-agonist increased the inhibitory effect of tested PDE inhibitors on the production of IFN-gamma 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.
我们研究了药物，尤其是抗肺部疾病药物，对人外周血单个核细胞（PBMC）细胞因子产生的影响。罗红霉素（RXM）是一种具有14元大环结构的大环内酯类抗生素，它可增加贴壁细胞（单核细胞/巨噬细胞），但抑制了植物血凝素（PHA）刺激的PBMC的增殖。RXM以剂量依赖的方式抑制脂多糖（LPS）刺激的PBMC产生IL-1β和TNF-α。左氧氟沙星是一种氟喹诺酮类药物，可增加PHA刺激的PBMC产生IL-2。在高浓度左氧氟沙星（LVFX）时，GM-CSF和可溶性IL-2受体的产生受到抑制。LVFX抑制IL-1β的产生，但不抑制TNF-α的产生和IL-8的产生。β-肾上腺素能受体激动剂（β-激动剂）丙卡特罗、克仑特罗、非诺特罗和特布他林抑制TNF-和IL-1β的产生。二丁酰环磷腺苷（dbcAMP）几乎完全抑制TNF-α的产生，而即使在检测的最高浓度下，IL-1β的产生似乎也部分耐受。丙卡特罗和茶碱均可提高LPS刺激的PBMC中的cAMP水平，但丙卡特罗的作用有限。丙卡特罗与茶碱对TNF-α和IL-1β产生的抑制作用呈相加增强。在所检测的磷酸二酯酶（PDE）同工酶抑制剂中，IV型PDE抑制剂比非选择性的、III型或III/IV型抑制剂更有效地抑制LPS刺激的PBMC产生TNF-α和IL-1β。添加β-激动剂可增强所检测的PDE抑制剂对TNF-α和IL-1β产生的抑制作用。IV型、III型和非选择性PDE抑制剂以剂量依赖的方式有效抑制IFN-γ和IL-2的产生。相比之下，仅最高浓度的IV型抑制剂可抑制IL-4和IL-5的产生，其他药物对其产生无影响。同样，dbcAMP对IFN-γ和IL-2产生的抑制作用比对IL-4和IL-5的抑制作用更强。添加β-激动剂可增强所检测的PDE抑制剂对IFN-γ和IL-2产生的抑制作用。这些发现表明，这些药物对PBMC细胞因子的产生具有免疫调节作用，也表明它们可能是治疗多种细胞因子为重要病因的疾病的有效药理药物。
