Statins enhance the anti-inflammatory effects of inhaled corticosteroids in asthmatic patients through increased induction of indoleamine 2, 3-dioxygenase.

BACKGROUND We have previously shown that inhaled corticosteroids activate indoleamine 2, 3-dioxygenase (IDO) activity through increased IL-10 secretion. Statins might enhance the anti-inflammatory effects of corticosteroids. OBJECTIVE In a double-blind study we added simvastatin to patients with mild asthma receiving a low dose of inhaled budesonide and evaluated sputum eosinophil counts, IL-10 secretion, and IDO activity, as well as their putative signaling pathways. METHODS After a 2-week run-in period without treatment, 50 asthmatic patients were treated with 200 μg of budesonide and randomly assigned to either 10 mg of simvastatin or matched placebo for 8 weeks. Inflammation was evaluated through eosinophil counts, secretory signaling molecules, and immunocytochemistry of macrophages in sputum. RESULTS Sputum eosinophil percentages were reduced significantly by the combined therapy with budesonide and simvastatin compared with budesonide alone (P = .02). Corticosteroids activated glucocorticoid-induced TNF receptor ligand, which induces activation of p52 through the noncanonical nuclear factor κB pathway, leading to the increased transcription and activation of IDO. Simvastatin enhanced corticosteroid-activated noncanonical nuclear factor κB-dependent induction of IDO by activating type I interferons and also enhanced the effect of corticosteroid on IL-10 release. CONCLUSION A statin enhances the anti-inflammatory effect of an inhaled corticosteroid in asthma, and this was mediated through the alteration of IDO activity in macrophages.

[1]  G. Prendergast,et al.  Inhibition of indoleamine 2,3-dioxygenase, an immunoregulatory target of the cancer suppression gene Bin1, potentiates cancer chemotherapy , 2005, Nature Medicine.

[2]  Jai Youl Ro,et al.  Anti-inflammatory mechanism of simvastatin in mouse allergic asthma model. , 2007, European journal of pharmacology.

[3]  I. Pavord,et al.  Effects of montelukast compared to double dose budesonide on airway inflammation and asthma control. , 2007, Respiratory medicine.

[4]  J. Last,et al.  Simvastatin inhibits airway hyperreactivity: implications for the mevalonate pathway and beyond. , 2009, American journal of respiratory and critical care medicine.

[5]  L. Pfeffer,et al.  Interferon induces NF-kappa B-inducing kinase/tumor necrosis factor receptor-associated factor-dependent NF-kappa B activation to promote cell survival. , 2005, The Journal of biological chemistry.

[6]  Toby Lawrence,et al.  IKKα limits macrophage NF-κB activation and contributes to the resolution of inflammation , 2005, Nature.

[7]  H. Perlman,et al.  Simvastatin Treatment Ameliorates Autoimmune Disease Associated with Accelerated Atherosclerosis in a Murine Lupus Model1 , 2006, The Journal of Immunology.

[8]  D. Munn,et al.  Ido expression by dendritic cells: tolerance and tryptophan catabolism , 2004, Nature Reviews Immunology.

[9]  I. Adcock,et al.  How Do Corticosteroids Work in Asthma? , 2003, Annals of Internal Medicine.

[10]  P. Barnes,et al.  Sputum indoleamine-2, 3-dioxygenase activity is increased in asthmatic airways by using inhaled corticosteroids. , 2008, The Journal of allergy and clinical immunology.

[11]  D. Munn,et al.  Prevention of T cell–driven complement activation and inflammation by tryptophan catabolism during pregnancy , 2001, Nature Immunology.

[12]  N. Thomson,et al.  A Novel Anti-Inflammatory Role of Simvastatin in a Murine Model of Allergic Asthma1 , 2004, The Journal of Immunology.

[13]  D. Keskin,et al.  Potential Regulatory Function of Human Dendritic Cells Expressing Indoleamine 2,3-Dioxygenase , 2002, Science.

[14]  Toby Lawrence,et al.  IKKalpha limits macrophage NF-kappaB activation and contributes to the resolution of inflammation. , 2005, Nature.

[15]  V. Kozlov,et al.  Changes in disease activity, cytokine production, and proliferation of peripheral blood mononuclear cells in patients with rheumatoid arthritis after simvastatin treatment , 2009, Scandinavian journal of rheumatology.

[16]  L. Steinman,et al.  Cholesterol-lowering statins possess anti-inflammatory activity that might be useful for treatment of MS. , 2002, Neurology.

[17]  M. Karin,et al.  The two NF-kappaB activation pathways and their role in innate and adaptive immunity. , 2004, Trends in immunology.

[18]  I. Adcock,et al.  Loss of control of asthma following inhaled corticosteroid withdrawal is associated with increased sputum interleukin-8 and neutrophils. , 2007, Chest.

[19]  Gerhard Opelz,et al.  Inhibition of Allogeneic T Cell Proliferation by Indoleamine 2,3-Dioxygenase–expressing Dendritic Cells , 2002, The Journal of experimental medicine.

[20]  S. Youssef,et al.  The HMG-CoA reductase inhibitor, atorvastatin, promotes a Th2 bias and reverses paralysis in central nervous system autoimmune disease , 2002, Nature.

[21]  L. Pfeffer,et al.  Interferon Induces NF-κB-inducing Kinase/Tumor Necrosis Factor Receptor-associated Factor-dependent NF-κB Activation to Promote Cell Survival* , 2005, Journal of Biological Chemistry.

[22]  Malcolm Johnson,et al.  Glucocorticoid receptor nuclear translocation in airway cells after inhaled combination therapy. , 2005, American journal of respiratory and critical care medicine.

[23]  M. Karin,et al.  The two NF-κB activation pathways and their role in innate and adaptive immunity , 2004 .

[24]  D. Munn,et al.  Inhibition of  T Cell Proliferation by Macrophage Tryptophan Catabolism , 1999, The Journal of experimental medicine.

[25]  L. Boon,et al.  Reverse signaling through GITR ligand enables dexamethasone to activate IDO in allergy , 2007, Nature Medicine.