Theophylline at therapeutic concentrations inhibits NF-kappa B activation in human lung mast cells

Inflammation of the airways is a cardinal feature of asthma. It has recentl y been recognized that mast cells may contribute to this process by cytokin e secretion. Activation of a number of transcription factors, such as NF-ka ppaB, results in the de novo synthesis of a wide spectrum of cytokines incl uding TNF alpha, IL-8 and GM-CSF. We have assessed the activation of NF-kap paB by exposure of purified lung mast cells to TNF alpha (5 ng/ml), SCF (10 ng/ml) and anti-IgE (1 mug/ml). Mast cells were identified by cytospin imm unocytochemistry using the antitryptase antibody AA-1 and activated NF-kapp aB visualized by the antibody 2c7 (Upjohn) which recognizes a site revealed only on its dissociation from 1-kappaB. In addition, the effects of theoph ylline and other modulatory drugs have been era mined on NF-kappaB activati on and consequential cytokine secretion. Results show that TNF alpha increa sed the percentage of cells staining positive for activated NF-kappaB from 8.4 +/- 4.8 to 63 +/- 4.5 within 15 min. Anti-IgE caused a slow increase fr om 4.3 +/- 0.4 to 45.4 +/- 13.3% at 4 h. Theophylline at 20 mug/ml decrease d TNF alpha and anti-IgE induced NF-kappaB activation by 37.3 +/- 2.1 and 2 5.3 +/- 1.3%, respectively. Secretion of TNF alpha, IL-8 and GM-CSF was als o inhibited by 20 mug/ml theophylline. The suppression of NF-kappaB activat ion indicates that theophylline, in addition to its bronchodilator actions, has anti-inflammatory activity which is likely to be pertinent to the trea tment of bronchial asthma. Copyright (C) 2001 S. Karger AG, Basel.