Low-dose theophylline does not exert its anti-inflammatory effects in mild asthma through upregulation of interleukin-10 in alveolar macrophages

Background: There is accumulating evidence that theophylline has antiinflammatory or immunomodulatory effects. This may be, in part, mediated via an upregulation in the production of the anti-inflammatory cytokine interleukin (IL)-10. We determined whether low-dose theophylline (LDT) would increase the production of IL-10, and attenuate the production of proinflammatory cytokines by alveolar macrophages. Methods: In a double-blind. placebo-con trolled, crossover study involving 15 steroid-free patients with mild asthma, fiberoptic bronchoscopy and broncho alveolar lavage (BAL) were performed at the end of the treatment and placebo periods. Alveolar macrophages were cultured in vitro, and we measured their release of IL-10, GM-CSF, and TNF-alpha. We also measured IL-10 production in whole blood together with the number of monocytes and T cells expressing intracellular IL-10 by flow cytometry. Results: LDT did not increase the production of IL-10, or attenuate the production of GM-CSF or TNF-alpha by alveolar macrophages. However, after theophylline treatment, there was a significant reduction in mean (SD) (95% CI) BAL eosinophil number from 3.4 (1.7)% (95% CI 2.4-4.4) to 1.7 (1.0)% (95% CI 1.1-2.3) compared with placebo (P <0.05). Similarly, there was no increase in whole-blood IL-10 release or in the number of monocytes and T cells expressing intracellular IL-10 after treatment. Conclusions: LDT has an anti-inflammatory effect in asthma; however, this effect is not mediated via the production or IL-10 or the attenuation of GM-CSF or TNF-alpha. The mechanisms of theophylline activity remain to be determined.