Corticosteroids partially suppress
cytokine production by
chronic obstructive pulmonary disease (
COPD) alveolar macrophages.
p38 mitogen-activated protein kinase (MAPK) inhibitors are a novel class of anti-inflammatory drug. We have studied the effects of combined treatment with a
corticosteroid and a
p38 MAPK inhibitor on
cytokine production by
COPD alveolar macrophages, with the aim of investigating dose-sparing and efficacy-enhancing effects. Alveolar macrophages from 10 patients with
COPD, six smokers, and six nonsmokers were stimulated with
lipopolysaccharide (LPS) after preincubation with five concentrations of
dexamethasone alone, five concentrations of the
p38 MAPK inhibitor 1-(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-3(4-(2-morpholin-4-yl-ethoxy)naphthalen-1-yl)urea (BIRB-796) alone, and all combinations of these concentrations. After 24 h, the supernatants were analyzed for
interleukin (IL)-8,
IL-6,
tumor necrosis factor α (TNFα),
granulocyte macrophage-colony-stimulating factor (
GM-CSF), IL-1α, IL-1β,
IL-1ra,
IL-10,
monocyte chemoattractant protein 3,
macrophage-derived chemokine (MDC), and regulated on activation normal T cell expressed and secreted (
RANTES). The effect of
dexamethasone on
p38 MAPK activation was analyzed by Western blotting.
Dexamethasone and
BIRB-796 both reduced LPS-induced
cytokine production in a dose-dependent manner in all subject groups, with no differences between groups. Increasing the concentration of
BIRB-796 in combination with
dexamethasone produced progressively greater inhibition of
cytokine production than
dexamethasone alone. There were significant efficacy-enhancing benefits and synergistic dose-sparing effects (p < 0.05) for the combination treatment for
IL-8,
IL-6, TNFα,
GM-CSF,
IL-1ra,
IL-10, MDC, and
RANTES in one or more subject groups.
Dexamethasone had no effect on LPS-induced
p38 MAPK activation. We conclude that
p38 MAPK activation in alveolar macrophages is
corticosteroid-insensitive. Combining a
p38 MAPK inhibitor with a
corticosteroid synergistically enhances the anti-inflammatory effects on LPS-mediated
cytokine production by alveolar macrophages from patients with
COPD and controls.