Targeting phosphoinositide-3-kinase-delta with theophylline reverses corticosteroid insensitivity in chronic obstructive pulmonary disease

Am J Respir Crit Care Med. 2010 Oct 1;182(7):897-904. doi: 10.1164/rccm.200906-0937OC. Epub 2010 Mar 11.


Rationale: Patients with chronic obstructive pulmonary disease (COPD) show a poor response to corticosteroids. This has been linked to a reduction of histone deacetylase-2 as a result of oxidative stress and is reversed by theophylline.

Objectives: To determine the role of phosphoinositide-3-kinase-delta (PI3K-δ) on the development of corticosteroid insensitivity in COPD and under oxidative stress, and as a target for theophylline.

Methods: Corticosteroid sensitivity was determined as the 50% inhibitory concentration of dexamethasone on tumor necrosis factor-α-induced interleukin-8 release in peripheral blood mononuclear cells from patients with COPD (n = 17) and compared with that of nonsmoking (n = 8) and smoking (n = 7) control subjects. The effect of theophylline and a selective PI3K-δ inhibitor (IC87114) on restoration of corticosteroid sensitivity was confirmed in cigarette smoke-exposed mice.

Measurements and main results: Peripheral blood mononuclear cells of COPD (50% inhibitory concentration of dexamethasone: 156.8 ± 32.6 nM) were less corticosteroid sensitive than those of nonsmoking (41.2 ± 10.5 nM; P = 0.018) and smoking control subjects (47.5 ± 19.6 nM; P = 0.031). Corticosteroid insensitivity and reduced histone deacetylase-2 activity after oxidative stress were reversed by a non-selective PI3K inhibitor (LY294002) and low concentrations of theophylline. Theophylline was a potent selective inhibitor of oxidant-activated PI3K-δ, which was up-regulated in peripheral lung tissue of patients with COPD. Furthermore, cells with knock-down of PI3K-δ failed to develop corticosteroid insensitivity with oxidative stress. Both theophylline and IC87114, combined with dexamethasone, inhibited corticosteroid-insensitive lung inflammation in cigarette-smoke-exposed mice in vivo.

Conclusions: Inhibition of oxidative stress dependent PI3K-δ activation by a selective inhibitor or theophylline provides a novel approach to reversing corticosteroid insensitivity in COPD.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenine / analogs & derivatives
  • Adenine / pharmacology
  • Animals
  • Anti-Inflammatory Agents / pharmacology*
  • Case-Control Studies
  • Dexamethasone / pharmacology*
  • Drug Resistance / drug effects*
  • Drug Resistance / genetics
  • Histone Deacetylase 2 / metabolism
  • Humans
  • Leukocytes, Mononuclear
  • Mice
  • Oxidative Stress
  • Phosphodiesterase Inhibitors / pharmacology
  • Phosphodiesterase Inhibitors / therapeutic use*
  • Phosphoinositide-3 Kinase Inhibitors*
  • Pulmonary Disease, Chronic Obstructive / drug therapy*
  • Quinazolines / pharmacology
  • RNA Interference
  • Smoking / adverse effects
  • Theophylline / pharmacology
  • Theophylline / therapeutic use*
  • Tobacco Smoke Pollution


  • Anti-Inflammatory Agents
  • IC 87114
  • Phosphodiesterase Inhibitors
  • Phosphoinositide-3 Kinase Inhibitors
  • Quinazolines
  • Tobacco Smoke Pollution
  • Dexamethasone
  • Theophylline
  • Histone Deacetylase 2
  • Adenine