Salmeterol inhibits interferon-gamma and interleukin-4 production by human peripheral blood mononuclear cells.
T-lymphocytes play an important role in allergic asthma. In the present study, the effect of beta(2)-adrenoceptor agonists was examined on proliferation, interleukin-4 (IL-4) and interferon-gamma (IFN-gamma) production by human peripheral blood mononuclear cells (PBMC). The proliferation after 24 h phytohaemagglutinin (PHA) activation was significantly inhibited at high concentrations of salmeterol, isoprenaline and salbutamol (> or = 10(-6) M). A U-shaped concentration response curve was observed for the effect of all agonists on IL-4 production 24 h after PHA activation. Maximal inhibition occurred at 10(-9) M and amounted to 71% (P < 0.02), 38% (P < 0.01) and 49% (P < 0.01) for salmeterol, isoprenaline and salbutamol, respectively. In contrast, no significant effect of salmeterol (10(-11)-10(-5) M) on IL-4 production could be detected after 96 h. A biphasic concentration response curve was observed for the inhibitory activity of all beta-adrenoceptor agonists on IFN-gamma production by PBMC 24 h after PHA activation. The first phase reached a plateau at 10(-9) M and the inhibition amounted to 50% (P < 0.05), 33% (P < 0.01) and 44% (P < 0.05) for salmeterol, isoprenaline and salbutamol, respectively. At higher concentrations of the three beta-adrenoceptor agonists the inhibition was increased up to 80% (P < 0.05), 60% (P < 0.05) and 58% (P < 0.01), respectively. Similar to the results obtained after 24 h, IFN-gamma production after 96 h was biphasically inhibited by salmeterol, and this inhibition (60%) was significantly at 10(-5) M. Together, the present data provide clear evidence for concentration-dependent effects of beta-adrenoceptor agonists on the IL-4 and IFN-gamma production by human PBMC. These results suggest that beta-agonists, at low concentrations, predominantly inhibit IL-4 production and may therefore act as anti-inflammatory drugs in allergic asthma.
Mohede
I C
IC
Department of Pharmacology, Utrecht Institute of Pharmaceutical Sciences, Utrecht University, The Netherlands.
Van Ark
I
I
Brons
F M
FM
Van Oosterhout
A J
AJ
Nijkamp
F P
FP
D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000420:Albuterol / Q000031:analogs & derivatives* / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis*; D015847:Interleukin-4 / Q000096:biosynthesis*; D007545:Isoproterenol / Q000494:pharmacology; D007963:Leukocytes, Mononuclear / Q000187:drug effects* / Q000378:metabolism; D010835:Phytohemagglutinins; D000068299:Salmeterol Xinafoate
D000318:Adrenergic beta-Agonists; D010835:Phytohemagglutinins; D015847:Interleukin-4; D000068299:Salmeterol Xinafoate; D007371:Interferon-gamma; D007545:Isoproterenol; D000420:Albuterol