A molecular mechanism of action of theophylline: Induction of histone deacetylase activity to decrease inflammatory gene expression

Abstract

The molecular mechanism for the anti-inflammatory action of theophylline is currently unknown, but low-dose theophylline is an effective add-on therapy to corticosteroids in controlling asthma. Corticosteroids act, at least in part, by recruitment of histone deacetylases (HDACs) to the site of active inflammatory gene transcription. They thereby inhibit the acetylation of core histones that is necessary for inflammatory gene transcription. We show both in vitro and in vivo that low-dose theophylline enhances HDAC activity in epithelial cells and macrophages. This increased HDAC activity is then available for corticosteroid recruitment and predicts a cooperative interaction between corticosteroids and theophylline. This mechanism occurs at therapeutic concentrations of theophylline and is dissociated from phosphodiesterase inhibition (the mechanism of bronchodilation) or the blockade of adenosine receptors, which are partially responsible for its side effects. Thus we have shown that low-dose theophylline exerts an antiasthma effect through increasing activation of HDAC which is subsequently recruited by corticosteroids to suppress inflammatory genes.macrophages ͉ corticosteroids ͉ histone deacetylation ͉ granulocytemacrophage colony-stimulating factor

How Do Corticosteroids Work in Asthma?

“…Accumulating evidence indicates that at lower doses, theophylline has anti-inflammatory effects, but these are probably not mediated by phosphodiesterase inhibition because the inhibition of these enzymes is trivial at low plasma concentrations that are clinically effective (49). We have recently shown that the anti-inflammatory effects of theophylline may be mediated via activation of HDAC and that this effect is independent of phosphodiesterase inhibition (50). Low doses of theophylline significantly increase HDAC activity in bronchial biopsy specimens from asthmatic patients, and the increase in HDAC activity is correlated with the reduction in airway eosinophils (50).…”

“…We have recently shown that the anti-inflammatory effects of theophylline may be mediated via activation of HDAC and that this effect is independent of phosphodiesterase inhibition (50). Low doses of theophylline significantly increase HDAC activity in bronchial biopsy specimens from asthmatic patients, and the increase in HDAC activity is correlated with the reduction in airway eosinophils (50). Because corticosteroids also activate HDAC, but via a different mechanism, theophylline should enhance the anti-inflammatory actions of corticosteroids; this enhancement occurs because the HDAC recruited to the inflammatory gene will be more effective at switching off the gene.…”

“…Because corticosteroids also activate HDAC, but via a different mechanism, theophylline should enhance the anti-inflammatory actions of corticosteroids; this enhancement occurs because the HDAC recruited to the inflammatory gene will be more effective at switching off the gene. Indeed, therapeutic concentrations of theophylline markedly potentiate the anti-inflammatory effects of corticosteroids in vitro (50). This effect may explain why adding a low dose of theophylline is more effective than increasing the dose of inhaled corticosteroids in patients whose asthma is not adequately controlled (51-53).…”

“…Other means of activating HDACs may have therapeutic potential, and theophylline is the first drug that has been shown to have this property; the result is a marked potentiation of the anti-inflammatory effects of corticosteroids. This action of theophylline is not mediated via phosphodiesterase inhibition or adenosine receptor antagonism and, therefore, seems to be a novel action of theophylline (50). It may be possible to discover other drugs in this class, and they could form the basis of a new class of anti-inflammatory drugs without the side effects that limit the use of theophylline (49).…”

Stability Evaluation of Caffeine-8-Thioglicolic Acid Amides, With Determined Antihypoxic Effects

“…Substituted xanthine derivatives are a class of biologically active substances that are well-defined and widely studied in terms of their pharmacological activity as adenosine receptor antagonists, phosphodiesterase inhibitors, and inducers of histone deacetylase activity (Kalla et al, 2006;Lin et al, 2006;Ito et al, 2002). Due to these and several other known factors, this group have become broadly used in medicine not only as agents affecting the central nervous system, but also as active substances in the field of asthma, bronchitis, and chronic obstructive pulmonary diseases and as diuretics, cardiac stimulants, and renal protective agents (Caramori et al, 2003;Dal Piaz & Giavannoni, 2000;Kiesman et al, 2006).…”