Curcumin restores corticosteroid function in monocytes exposed to oxidants by maintaining HDAC2.
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 EC(50) 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 muM 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.
Meja
Koremu K
KK
Novartis Institutes for Biomedical Research, Respiratory Disease, Horsham, UK.
Rajendrasozhan
Saravanan
S
Adenuga
David
D
Biswas
Saibal K
SK
Sundar
Isaac K
IK
Spooner
Gillian
G
Marwick
John A
JA
Chakravarty
Probir
P
Fletcher
Danielle
D
Whittaker
Paul
P
Megson
Ian L
IL
Kirkham
Paul A
PA
Rahman
Irfan
I
D000305:Adrenal Cortex Hormones / Q000494:pharmacology / Q000502:physiology*; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology*; D003474:Curcumin / Q000494:pharmacology*; D003513:Cycloheximide / Q000494:pharmacology; D004578:Electron Spin Resonance Spectroscopy; D056464:Histone Deacetylase 2; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D009000:Monocytes / Q000187:drug effects* / Q000201:enzymology; D020411:Oligonucleotide Array Sequence Analysis; D016877:Oxidants / Q000494:pharmacology*; D018384:Oxidative Stress; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D029424:Pulmonary Disease, Chronic Obstructive / Q000201:enzymology / Q000209:etiology; D012097:Repressor Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012906:Smoke / Q000009:adverse effects*; D012907:Smoking / Q000009:adverse effects; D014026:Nicotiana; D020298:U937 Cells
D000305:Adrenal Cortex Hormones; D000894:Anti-Inflammatory Agents, Non-Steroidal; D000975:Antioxidants; D056572:Histone Deacetylase Inhibitors; D016877:Oxidants; D011500:Protein Synthesis Inhibitors; D012097:Repressor Proteins; D012906:Smoke; D003513:Cycloheximide; D056464:Histone Deacetylase 2; D006655:Histone Deacetylases; D003474:Curcumin