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

Lead Research Organisation: Imperial College London
Department Name: National Heart and Lung Institute

Abstract

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,

Technical Summary

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.

Publications

10 25 50
 
Description Member of ERS/ATS Task Force on severe asthma
Geographic Reach Multiple continents/international 
Policy Influence Type Membership of a guidance committee
 
Description Centre
Amount £2,240,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 10/2011 
End 09/2015
 
Description Project
Amount £50,000 (GBP)
Organisation Asthma UK 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2010 
End 09/2011
 
Description Centre 
Organisation King's College London
Department School of Medicine KCL
Country United Kingdom 
Sector Academic/University 
PI Contribution Greater understanding of T-cell regulation in severe asthma. Further understandign of steroid responses in severe asthma.
Collaborator Contribution Enhanced my ability to examine chromatin changes in human T-cells by collaboration with Dr Lavender and Cousins. Access to deep sequencing capacity through MRC Centre and BRC.
Impact Other than contribution to Centre no grant/papers as yet. Expected 2011. Joint PhD student.
Start Year 2008
 
Description IUAP AIReWAY II 
Organisation University of Ghent
Department Faculty of Medicine
Country Belgium 
Sector Academic/University 
PI Contribution Investigation of the effect of airway infections on animal models and in vitro human primary cell models of asthma and COPD. We will be looking at effects of viral infection of human epithelial cells using SILAC approaches and on innate immune cells in an ozone model of COPD after infection.
Collaborator Contribution Large range of in vitro and in vivo models to look at interaction of bacterial and viral infection on allergen challenge and cigarette smoke models
Impact none to date - just started
Start Year 2012
 
Description UBIOPRED 
Organisation European Commission
Department Innovative Medicines Initiative (IMI)
Country European Union (EU) 
Sector Multiple 
PI Contribution I run WP6 which aims to get improved murine models of severe asthma and examines steroid responses in cells from severe asthma
Collaborator Contribution Other Workpackages cover the following: Patient cohort collection, SOPs, definition of patient groups, Management, ethics, publication, bronchoscopy, 'omics analysis and systems analysis.
Impact Patient collection and initial handprint analysis performed. Beginning to measure human handprints with murine and cell model handprints. PubMed PMID: 22630041. PubMed PMID: 21106547.
Start Year 2009
 
Description Bring Your Child to Work Day at NHLI 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact Described in the following website:

http://www1.imperial.ac.uk/nhli/aboutus/child_to_work_day/ -


Great interest in the children. Encouraged discussion of life-work balance between colleagues with children.
Interest to run similar programmes in local schools.
Year(s) Of Engagement Activity 2013,2014,2015
URL http://www1.imperial.ac.uk/nhli/aboutus/child_to_work_day/
 
Description Hakathon for developing new devices for respiratory diseases 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Industry/Business
Results and Impact Interactive meeting at Imperial College and beamed to MIT (Cambridge, USA) to discuss new monitoring devices for patients with lung diseases such as COPD. Involved discussion about patients needs with engineers scientists and doctors. Received a lot of national publicity.
Year(s) Of Engagement Activity 2015
URL http://www3.imperial.ac.uk/newsandeventspggrp/imperialcollege/eventssummary/event_7-9-2015-17-28-1
 
Description Heart & Lung Shop 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Details provided on the following website:
http://www1.imperial.ac.uk/nhli/public_engagement/the_curious_act/heart_and_lung_repair_shops/



High level of interest from the public in participating in clinical trials and in receiving more information. We plan to continue these popular events in the future.
Year(s) Of Engagement Activity 2014
URL http://www1.imperial.ac.uk/nhli/public_engagement/the_curious_act/heart_and_lung_repair_shops/
 
Description Imperial College Festival 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? Yes
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Excellent feedback over 2 days regarding impact of asthma and COPD on everyday life of people

arranged visit to school
Year(s) Of Engagement Activity 2012,2013,2014
 
Description Imperial Festival 2012 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Described in the following website:
http://www3.imperial.ac.uk/festival/previousfestivals/imperialfestival2012

Increased public awareness about lung disease, particularly COPD. Engagement of children with a locally devised COPD board game.
Year(s) Of Engagement Activity 2012
URL http://www3.imperial.ac.uk/festival/previousfestivals/imperialfestival2012
 
Description Laboratory Placement for final year school pupils 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact 2 week placement visit to different laboratories and hospital laboratories.
Year(s) Of Engagement Activity 2015
 
Description Patient and volunteer engagement 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Study participants or study members
Results and Impact 2 Open Days that invited all patients and normal control subjects to present our research and to get feedback and answer questions from study participants. Very positive feedback from the meeting and more are planned.
Year(s) Of Engagement Activity 2016
 
Description UBIOPRED patient interaction 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Participants in your research and patient groups
Results and Impact Annual UBIOPRED Meeting invites representatives of asthma patient groups from across EU. We work with them to discuss priorities for future work and patient involvement
I discussed work with Asthma UK regarding research into how steroids work in asthma and why understanding differences in severe asthma are important

Altered clinical trial to use different group of patients
Year(s) Of Engagement Activity 2010,2011,2012,2013,2014