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

Abstract

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 mM 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.

Andrographolide Restores Steroid Sensitivity To Block Lipopolysaccharide/IFN-γ–Induced IL-27 and Airway Hyperresponsiveness in Mice

“…In the present study, we observed a major drop in nuclear HDAC2 level and total HDAC activity and an increase of the total HAT/HDAC activity ratio upon LPS/IFN-g stimulation, which might be responsible for LPS/IFN-g-induced steroid insensitivity. A number of studies have shown that oxidative and nitrative stress could promote HDAC2 degradation via nitration, carbonylation, or phosphorylation (26,27,46). We detected prominent serine phosphorylation of HDAC2 in Raw 264.7 cells in response to LPS/ IFN-g, which might subsequently contribute to its own degradation.…”

Curcumin: an orally bioavailable blocker of TNF and other pro‐inflammatory biomarkers

“…Eosinophilia in the curcumin-treated mice was markedly reduced, as was the expression of the co-stimulatory molecules (CD80, CD86 and OX40L) on antigen-presenting cells, and expression of MMP-9, ornithine amino transferase and thymic stromal lymphopoietin genes was also attenuated. Thirdly, curcumin was found to reverse corticosteroid resistance in monocytes exposed to oxidants by maintaining histone deacetylase-2 activity (Meja et al, 2008). Although no clinical data are available yet, all of these pre-clinical studies suggest that curcumin has potential as a therapeutic for asthma.…”

Scarless wound healing gel with Binahong (Anredera cordifolia (Ten) Steenis) leaves extract and celecoxib as the active ingredients

“…Celecoxib is suggested to play a role in the inflammation phase (1 st phase) of the wound healing processes [2,8]. Both ursolic acid and celecoxib inhibit inflammation mediator prostaglandins [9][10][11]. As phytosterol, ursolic acid inhibits phospholipase [11] while celecoxib inhibits COX-2 [12,13] in the cascade of prostaglandin synthase [2,12,14,15].…”