DiagnosticsNovel Mechanism Of Action Of Corticosteroids In Allergic Diseases
Research by Peter Barnes (Imperial College, London) and colleagues may
explain the effectiveness of common treatments for allergic inflammation
and
may point the way to targets for new treatments for allergic diseases,
according to a study published in this week"s open-access journal PLoS
Medicine.
Allergic diseases - which affect about 50 million people a year in the US
alone - are triggered when the immune system responds to a normally
harmless material by activating a specific type of T lymphocyte called a T
helper-2 cell (Th2). The Th2 cells make three cytokines, which are
responsible for the inflammation associated with allergies.
Corticosteroids are often used to treat allergic inflammation but it is
not well
understood how these corticosteroids work to inhibit the expression of Th2
cytokines.
Using laboratory experiments and tests in seven patients with mild asthma,
Peter Barnes and colleagues suggest that corticosteroids inhibit the
expression of Th2 cytokines and thus reduce allergic inflammation through
two interacting mechanisms which both prevent the nuclear translocation of
GATA-3, a key regulator of cytokine expression. Firstly, they suggest that
corticosteroids compete with GATA-3 for binding to the nuclear import
protein importin-í±. Secondly, they suggest that corticosteroids prevent
the phosphorylation of GATA-3, further preventing GATA-3 from binding to
importin-í±.
According to the authors, "This novel mechanism of action of
corticosteroids may account for the striking clinical efficacy of
corticosteroids in
the treatment of allergic diseases", although further experiments are
needed to show that the lymphocytes at the sites of allergic infection
respond
to corticosteroids in the same way as lymphocytes in the blood. In
addition, these findings suggest that interaction between phosphorylated
GATA-3 and
importin-í± may represent an important target for the development of new
therapies for the treatment of allergic diseases.
Funding: This study was supported by a grant from the Medical Research
Council and a non-restrictive grant from GlaxoSmithKline. The funders had
no
role in study design, data collection and analysis, decision to publish,
or preparation of the manuscript.
Citation:
"Suppression of GATA-3 Nuclear Import and Phosphorylation: A Novel Mechanism of Corticosteroid Action in Allergic Disease."
Maneechotesuwan K, Yao X, Ito K, Jazrawi E, Usmani OS, et al. (2009)
PLoS Med 6(5): e1000076. doi:10.1371/journal.pmed.1000076
Plos Medicine