Inhibitory Effects of Natural Flavones on Mast Cell and Keratinocyte Activation.
Abstract: Mast cells
are immune cells derived from the bone marrow that can rapidly release numerous
preformed and de novo-synthesized mediators like tumor necrosis factor (TNF), thereby
participating in various immune and inflammatory conditions. Recent evidence indicates
increased infiltration of mast cells in psoriatic lesional skin. Psoriasis (Ps) is an
autoimmune disease characterized by ... read morekeratinocyte hyperproliferation and chronic
inflammation, with increased expression of TNF and vascular endothelial growth factor
(VEGF). Keratinocytes can interact with dermal mast cells and participate in the
pathogenesis of Ps. Anti-TNF biological agents are more effective than traditional
treatments for Ps, but they are associated with increased risk of infections and blood
malignancies. In addition, these agents target inflammatory mediators after they are
released, and do not address keratinocyte hyperproliferation or activation. Thus, the
need for safe and effective treatments for Ps is still of major importance. Flavones are
plant-derived natural compounds with potent antioxidant and anti-inflammatory actions.
Flavones can also inhibit mast cell mediator release, but their precise mechanism of
action on human mast cells is not well understood, and their effect on human
keratinocytes has not been fully explored. In the present study, we investigated effects
of two flavones, luteolin and its structural analogue 3',4',5,7-tetramethoxyluteolin
(methoxyluteolin), on mediator release from human mast cells and keratinocytes. We
hypothesized that the two flavones inhibit activation and proliferation of mast cells
and keratinocytes, thereby providing novel benefits in the treatment for Ps. We show
that luteolin and methoxyluteolin are more potent than the only clinically available
"mast cell stabilizer" disodium cromoglycate (cromolyn), and block inflammatory mediator
production in human mast cells and keratinocytes. This inhibitory effect is mediated by
blocking intracellular calcium elevation, reducing mitochondrial translocation, and
decreasing NF-êB activation at both the transcriptional and translational levels.
The two flavones also decrease keratinocyte proliferation without affecting
intracellular energy production. Hence, luteolin and methoxyluteolin are promising
candidates for development of safer and more effective alternative therapies for the
treatment of skin diseases such as Ps, as well as other inflammatory
Thesis (Ph.D.)--Tufts University, 2014.
Submitted to the Dept. of Pharmacology & Experimental Therapeutics.
Advisors: Theoharis Theoharides, and John Castellot.
Committee: Louis Shuster, Angelo Azzi, and Aristidis Veves.
Keywords: Pharmacology, and Immunology.read less