ANTIINFLAMMATORY EFFECTS OF THEOPHYLLINE - MODULATION OF CYTOKINE PRODUCTION

Background: The basis for the efficacy of theophylline in the treatmen t of asthma remains enigmatic. Although commonly classified as a bronc hodilator, its ability to dilate smooth muscle is considered fairly po or and clinical responses are often independent of bronchodilatation. Recent studies have suggested that immunomodulatory activities may con tribute to the therapeutic benefit mediated by theophylline. Objective : We performed these preliminary studies to determine whether theophyl line modulates cytokine production by peripheral blood mononuclear cel ls. Methods: Peripheral blood mononuclear cells were obtained from 24 asthmatic subjects and were left in a resting state or stimulated with either mitogens (phytohemagglutinin, lipopolysaccharide) or antigen ( tetanus, cat) with or without the additional presence of theophylline (15 mu g/dL). Supernatants were collected and evaluated for cytokine c oncentration by ELISA. Results: Theophylline neither inhibited product ion of allergenic cytokines such as IL-4 nor modulated the repertoire of cytokines produced by T-H cells. A statistically significant inhibi tion of spontaneous interferon-gamma synthesis was observed (24.5 +/- 8.6 to 13.4 +/- 4.2; P < .05). Theophylline did have anti-inflammatory effects on cytokines primarily produced by mononuclear phagocytic cel ls. Theophylline mediated a slight inhibition of TNF-alpha production (0.26 +/- 0.08 to 0.21 +/- 0.06; P < .05). Theophylline was also assoc iated with a 2.8-fold increase in spontaneous production of the anti-i nflammatory cytokine IL-10 (0.35 +/- 0.08 to 0.98 +/- 0.16 ng; P < .01 ). Conclusions: A relative absence of IL-10 characterizes the asthmati c airways and may contribute to the development and severity of allerg ic inflammation. Induction of IL-10 production by theophylline may the refore mitigate inflammation and contribute to the clinical efficacy o f this class of medications.