Arthritis & Rheumatism, Volume 62,
November 2010 Abstract Supplement
Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Atlanta, Georgia November 6-11, 2010.
Investigation of the Effect of Histone Deacetylase 2 Function on Wegener's Granulomatosis.
Takagi1, Dai, Nakamaru2, Yuji, Akazawa2, Shigeru, Fukuda2, Satoshi
Department of Otolaryngology and Head & Neck Surgery Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido, Japan
Department of Otolaryngology and Head & Neck Surgery Hokkaido University Graduate School of Medicine
Wegener's Granulomatosis (WG) is a systemic vasculitic disease characterized by necrotizing granulomas and vasculitis of arterioles and venules. It has been reported that anti-neutrophil cytoplasmic antibodies (ANCA) activate neutrophils result in induction of glomerulonephritis in WG by released hydrogen peroxide.
Histone deacetylase (HDAC) deacetylates histone and deacetylation of histone associates with gene repression or gene silencing. Even more importantly, HDAC2 is also key molecule of steroid action, and this reduction causes steroid insensitive inflammation, which is seen in COPD, severe asthma, rheumatoid arthritis.
In this study, we investigated whether HDAC2 function decreased in WG patients, and effect of oxidative stress on function of HDAC2.
Patients and Methods:
A549 cells (lung epithelial cells) were stimulated by H2O2 (200 mM) to induce oxidative stress and expression of HDAC 2 were measured. We also measured HDAC 2 activity.
Six patients of WG (mean ± S.D. age 62 · 5 ± 17 · 5) diagnosed according to American College of Rheumatology criteria were examined.
Fresh PBMCs were isolated from heparinized blood by Ficoll-Conray separation and then whole cell protein was prepared. Target proteins were detected by Western blot analysis. We also measured HDAC 2 activity of PBMCs on patients.
Treatment of A549 cells with H2O2 did not suppress expression of HDAC2. However, treatment of H2O2 significantly decreased total HDAC2 activity (p < 0.05).
We found that HDAC 2 activity was significantly decreased in WG patients compared to those from healthy subjects (HS), 75.5±7.4 Arbitral Units at HS, 35.2±12.3 Arbitral Units at WG (p < 0.05). Furthermore, we found negative correlation between HDAC 2 activity and titer of c-reactive protein and titer of PR3-ANCA. However, expression of HDAC2 did not decreased in WG patients.
These results suggest that function of HDAC 2 is reduced in WG and that this reduction affects inflammation and vasculitis of WG. We have also confirmed that oxidative stress suppressed HDAC activity in lung epithelial cell line. Oxidative stress may worsen the disease via reduction of HDAC2 function without reduction of HDAC2 expression.
Thus, HDAC2 may serve therapeutic targets by modulating the function, which eventually regulates the development of WG.
To cite this abstract, please use the following information:
Takagi, Dai, Nakamaru, Yuji, Akazawa, Shigeru, Fukuda, Satoshi; Investigation of the Effect of Histone Deacetylase 2 Function on Wegener's Granulomatosis. [abstract]. Arthritis Rheum 2010;62 Suppl 10 :2029