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


OBJECTIVE
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.


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.
Airway Disease Section, NHLI Imperial College, London, United Kingdom.
Yasuo
Y
To
Kazuhiro
K
Ito
Yasuo
Y
Kizawa
Marco
M
Failla
Misako
M
Ito
Tadashi
T
Kusama
W Mark
WM
Elliott
James C
JC
Hogg
Ian M
IM
Adcock
Peter J
PJ
Barnes
D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D016022:Case-Control Studies; D003907:Dexamethasone / Q000494:pharmacology*; D004351:Drug Resistance / Q000187:drug effects* / Q000235:genetics; D056464:Histone Deacetylase 2 / Q000378:metabolism; D006801:Humans; D007963:Leukocytes, Mononuclear; D051379:Mice; D018384:Oxidative Stress; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy*; D011799:Quinazolines / Q000494:pharmacology; D034622:RNA Interference; D012907:Smoking / Q000009:adverse effects; D013806:Theophylline / Q000494:pharmacology / Q000627:therapeutic use*; D014028:Tobacco Smoke Pollution
D000893:Anti-Inflammatory Agents; C477872:IC 87114; D010726:Phosphodiesterase Inhibitors; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011799:Quinazolines; D014028:Tobacco Smoke Pollution; D003907:Dexamethasone; D013806:Theophylline; D056464:Histone Deacetylase 2; D000225:Adenine