Interactions between Theophylline and Salbutamol on Cytokine Release in Human Monocytes

Abstract

The combination of ␤ 2 -adrenoceptor agonists (␤ 2 -agonists) with inhaled steroids has become the standard treatment for mild to moderate asthma. Theophylline has also been combined successfully with inhaled steroids. However, the possible interaction between theophylline and ␤ 2 -agonists, with regard to their anti-inflammatory effects, has not been clarified. The aim of this study was to investigate the in vitro interaction between theophylline and salbutamol on cytokine generation from human monocytes and compare it with a similar interaction between dexamethasone and salbutamol. Purified monocytes from normal donors were pretreated with the drugs (alone or in combination) and stimulated with lipopolysaccharide for 24 h. Released tumor necrosis factor-␣ (TNF-␣) and interleukin-6 (IL-6), and their corresponding mRNA expressions, were determined and analyzed. Salbutamol (Ն 0.1 M) significantly inhibited the release of TNF-␣, but also significantly enhanced that of IL-6. In contrast, theophylline (50 M) and dexamethasone (0.1 M) strongly inhibited the generation of both cytokines. It is noteworthy that when the drugs were used in combination the effects of theophylline and salbutamol were additive in inhibiting TNF-␣ release, but theophylline blocked the IL-6-enhancing effect of salbutamol. A similar effect was seen when dexamethasone was combined with salbutamol. These results show that ␤ 2 -agonists have opposing effects on the generation of TNF-␣ and IL-6, but that when they were combined with clinically relevant concentrations of theophylline, theophylline, like dexamethasone, was capable of augmenting the anti-inflammatory effects of the ␤ 2 -agonists while at the same time preventing their proinflammatory effect. Thus, theophylline may have a potentially useful steroid-sparing effect.

Evaluation of the anti-inflammatory effects of β-adrenoceptor agonists on human lung macrophages

“…Studies investigating the effects of -agonists on monocytes, monocyte-derived macrophages (MDM) and macrophagelike cell lines suggest that these drugs may modulate a number of macrophage functions including the prevention of pro-inflammatory cytokine generation (Yoshimura et al, 1997;Izeboud et al, 1999;Donnelly et al, 2010;Shirato et al, 2013). By contrast, other studies show limited effects of -agonists in these systems (Linden, 1992;Zetturlund et al, 1998;Ezeamuzie and Shihab, 2010). As a consequence, no consistent evidence has emerged to determine whether -agonists effectively attenuate the pro-inflammatory activity of macrophages.…”

Antiallergic and Antiasthmatic Effects of a Novel Enhydrazinone Ester (CEE-1): Inhibition of Activation of Both Mast Cells and Eosinophils

“…The Western blot analysis of human eosinophils was performed according to methods routinely employed in our laboratory (Ezeamuzie and Shihab, 2010). Essentially, 800 ml of eosinophil suspension (2 Â 10 mixture].…”

Mepacrine treatment attenuates allergic airway remodeling segregated from airway inflammation in mice

“…We repurposed it for asthma due to its various pharmacological properties which are relevant to asthma. This approach was similar to efforts to repurpose other old drugs for asthma due to their new recognized activities [13,14]. The anti-asthmatic effects of mepacrine are presumably mediated through inhibition of PLA2 and TGF-β signaling [8,9].…”