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 anti-inflammatory 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-controlled, crossover study involving 15 steroid-free patients with mild asthma, fiberoptic bronchoscopy and bronchoalveolar 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 of IL-10 or the attenuation of GM-CSF or TNF-alpha. The mechanisms of theophylline activity remain to be determined.
Oliver
B
B
ANZAC Research Institute, University of Sydney, Sydney, Australia.
Tomita
K
K
Keller
A
A
Caramori
G
G
Adcock
I
I
Chung
K F
KF
Barnes
P J
PJ
Lim
S
S
D000328:Adult; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D001249:Asthma / Q000097:blood / Q000188:drug therapy*; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005260:Female; D005541:Forced Expiratory Volume / Q000187:drug effects; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000187:drug effects; D006801:Humans; D016753:Interleukin-10 / Q000097:blood* / Q000502:physiology; D016676:Macrophages, Alveolar / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D016210:Methacholine Chloride / Q000627:therapeutic use; D012720:Severity of Illness Index; D013806:Theophylline / Q000008:administration & dosage / Q000627:therapeutic use*; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
D000893:Anti-Inflammatory Agents; D014409:Tumor Necrosis Factor-alpha; D016210:Methacholine Chloride; D016753:Interleukin-10; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D013806:Theophylline