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Curcumin Restores Corticosteroid Function in Monocytes Exposed to Oxidants by Maintaining HDAC2

Koremu K. Meja^1,*, Saravanan Rajendrasozhan^2,*, David Adenuga², Saibal K. Biswas², Isaac K. Sundar², Gillian Spooner¹, John A. Marwick¹, Probir Chakravarty¹, Danielle Fletcher¹, Paul Whittaker¹, Ian L. Megson³, Paul A. Kirkham^1, and Irfan Rahman^2,

¹ Novartis Institute for Biomedical Research, Respiratory Diseases, Horsham, United Kingdom; ² Department of Environmental Medicine, Lung Biology and Disease Program, University of Rochester Medical Centre, Rochester, New York; and ³ Free Radical Research Facility, UHI, Millennium Institute, Inverness, United Kingdom

Correspondence and requests for reprints should be addressed to Paul A. Kirkham, PhD, Novartis Institutes for Biomedical Research, Respiratory Disease Area, Wimblehurst Road, Horsham, West Sussex RH12 5AB, UK. E-mail: paul.kirkham{at}novartis.com or Irfan_Rahman{at}urmc.rochester.edu

Oxidative stress as a result of cigarette smoking is an important etiologic factor in the pathogenesis of chronic obstructive pulmonary disease (COPD), a chronic steroid-insensitive inflammatory disease of the airways. Histone deacetylase-2 (HDAC2), a critical component of the corticosteroid anti-inflammatory action, is impaired in lungs of patients with COPD and correlates with disease severity. We demonstrate here that curcumin (diferuloylmethane), a dietary polyphenol, at nanomolar concentrations specifically restores cigarette smoke extract (CSE)- or oxidative stress–impaired HDAC2 activity and corticosteroid efficacy in vitro with an EC₅₀ of approximately 30 nM and 200 nM, respectively. CSE caused a reduction in HDAC2 protein expression that was restored by curcumin. This decrease in HDAC2 protein expression was reversed by curcumin even in the presence of cycloheximide, a protein synthesis inhibitor. The proteasomal inhibitor, MG132, also blocked CSE-induced HDAC2 degradation, increasing the levels of ubiquitinated HDAC2. Biochemical and gene chip analysis indicated that curcumin at concentrations up to 1 µM propagates its effect via antioxidant-independent mechanisms associated with the phosphorylation-ubiquitin-proteasome pathway. Thus curcumin acts at a post-translational level by maintaining both HDAC2 activity and expression, thereby reversing steroid insensitivity induced by either CSE or oxidative stress in monocytes. Curcumin may therefore have potential to reverse steroid resistance, which is common in patients with COPD and asthma.

Key Words: cigarette smoke • corticosteroid • macrophages • chronic obstructive pulmonary disease • polyphenols

CLINICAL RELEVANCE Curcumin, a dietary polyphenol, restores oxidative stress–impaired histone deacetylase-2 activity and corticosteroid efficacy in monocytes. Hence, curcumin has potential to reverse corticosteroid resistance, which is common in patients with chronic obstructive pulmonary disease and severe asthma.

 

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