Histone deacetylases (HDAC) are key
enzymes in the epigenetic control of gene expression. Recently, inhibitors of class I and class II HDAC have been successfully employed for the treatment of different inflammatory diseases such as
rheumatoid arthritis,
colitis, airway
inflammation and
asthma. So far, little is known so far about a similar
therapeutic effect of inhibitors specifically directed against
sirtuins, the class III HDAC. In this study, we investigated the expression and localization of endogenous
sirtuins in primary human dermal microvascular endothelial cells (HDMEC), a cell type playing a key role in the development and maintenance of skin
inflammation. We then examined the
biological activity of
sirtinol, a specific
sirtuin inhibitor, in HDMEC response to pro-inflammatory
cytokines. We found that, even though
sirtinol treatment alone affected only long-term cell proliferation, it diminishes HDMEC inflammatory responses to
tumor necrosis factor (TNF)α and
interleukin (IL)-1β. In fact,
sirtinol significantly reduced membrane expression of adhesion molecules in TNFã- or IL-1β-stimulated cells, as well as the amount of CXCL10 and CCL2 released by HDMEC following TNFα treatment. Notably,
sirtinol drastically decreased monocyte adhesion on activated HDMEC. Using selective inhibitors for
Sirt1 and
Sirt2, we showed a predominant involvement of
Sirt1 inhibition in the modulation of adhesion molecule expression and monocyte adhesion on activated HDMEC. Finally, we demonstrated the in vivo expression of
Sirt1 in the dermal vessels of normal and psoriatic skin. Altogether, these findings indicated that
sirtuins may represent a promising therapeutic target for the treatment of inflammatory
skin diseases characterized by a prominent microvessel involvement.