Regulation of IL-13 transcription in human T-cells by GATA-3/NF-AT complexes: modulation by corticosteroids

Asthma affects 1 in 12 of the UK population, with 5.2 million people currently receiving treatment. The UK has one of the highest prevalence of asthma in young adults in Europe and the numbers of children reporting asthma symptoms has risen six fold over the last 30 years. Asthma costs the NHS #889m per year and it is estimated that at least 12.7 million working days are lost due to asthma each year. The rising prevalence of allergic diseases and accompanying health care costs are therefore major health and socio-economic problems. Most asthmatic subjects respond to treatment with inhaled corticosteroids although the mechanisms underlying their action are not clear. We wish to determine how corticosteroids reduce the expression of key proteins involved in asthma particularly the inflammatory mediator interleukin 13 (IL-13). Understanding how corticosteroids work in mild asthma may help to develop new drugs to target these processes that have fewer side-effects and may be able to treat patients with severe asthma who do not improve with corticosteroids. This will result in improved patient care with less side-effects and in cost savings to the NHS,

Asthma affects 1 in 12 of the UK population, with 5.2 million people currently receiving treatment. Asthma costs the NHS #889m per year and it is estimated that at least 12.7 million working days are lost due to asthma each year. Inflammation in allergic diseases, such as asthma, is mediated via expression of the cytokines interleukin (IL)-4, IL-5 and IL-13 from T helper-2 (Th2) cells. These Th2 cytokines are regulated predominantly by the transcription factor GATA-3, which is mainly expressed in Th2 cells and is also responsible for their differentiation. GATA-3 is a phospho-protein whose activity is regulated by p38 mitogen activated protein kinase (MAPK).
Corticosteroids are highly effective in the treatment of allergic inflammation, with marked suppression of Th2 cytokines including IL-13 in asthmatic airways and in peripheral blood T-cells. In non-T-cells, corticosteroids mainly target nuclear factor kappaB (NF-?B); however, NF-?B does not control Th2 cytokine expression to any extent. We wish, therefore to examine how corticosteroids, acting through their receptor (GR), can suppress IL-13 release. We hypothesise that suppression of p38 MAPK activity and recruitment of HDAC2 to the GATA-3 complex plays a key role in GR-mediated repression of IL-13 transcription in human T-cells in vitro and in vivo. We propose that GR suppresses human IL-13 expression through pleitropic mechanisms including attenuation of GATA-3 phosphorylation and acetylation, competition for importins, prevention of NF-AT complex formation and induction of T-bet expression. We will examine this effect in human T-cells in vitro and ex vivo and also in vivo following exposure of mild asthmatic patients to inhaled corticosteroids.
These studies will provide mechanisms and pathways by which corticosteroids control IL-13 expression in human T-cells and may highlight p38 MAPK as a potential treatment for controlling Th2 cytokine expression in asthma.