Peter J. Barnes, FRS, FMedSci

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Presentation transcript:

Corticosteroid resistance in patients with asthma and chronic obstructive pulmonary disease Peter J. Barnes, FRS, FMedSci Journal of Allergy and Clinical Immunology Volume 131, Issue 3, Pages 636-645 (March 2013) DOI: 10.1016/j.jaci.2012.12.1564 Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 GRα phosphorylation at serine 226 (Ser226) impedes nuclear translocation, leading to steroid resistance. The GR can be phosphorylated by several kinases: p38MAPKα (p38α), which is activated by IL-2 and IL-4 or IL-13 and inhibited by p38MAPK inhibitors; JNK, which is activated by TNF-α; p38MAPK-γ (p38γ), which is also activated by IL-2 plus IL-4; and extracellular signal-regulated kinase (ERK), which is activated by staphylococcal enterotoxin B (SEB). These kinases are dephosphorylated by the phosphatases MKP-1 and PP2A, both of which are defective in cells from patients with severe asthma. PP2A is increased by the LABA formoterol. Journal of Allergy and Clinical Immunology 2013 131, 636-645DOI: (10.1016/j.jaci.2012.12.1564) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 Mechanism of reduced HDAC2 expression in patients with COPD, patients with severe asthma, and smokers with asthma. Oxidative stress activates PI3Kδ, which phosphorylates downstream kinases, such as Akt, resulting in the phosphorylation and inactivation of HDAC2. In addition, oxidative and nitrative stress generate peroxynitrite, which nitrates (NO) tyrosine residues (Tyr) on HDAC2 to inhibit its activity. These modifications of HDAC2 result in its ubiquitination (Ub), targeting the enzyme for degradation by the proteasome and leading to reduced expression and steroid resistance. Journal of Allergy and Clinical Immunology 2013 131, 636-645DOI: (10.1016/j.jaci.2012.12.1564) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 Steroid resistance as a result of oxidative stress can be reversed by several drugs that increase HDAC2 expression. HDAC2 activity is increased by theophylline and nortriptyline, which inhibit PI3Kδ; by antioxidants, including Nrf2 activators; and by macrolides, which target the PI3K pathway. In the future, drugs that directly activate HDAC2 might be discovered. Journal of Allergy and Clinical Immunology 2013 131, 636-645DOI: (10.1016/j.jaci.2012.12.1564) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions