Messenger RNA (mRNA) turnover is a crucial regulatory component of gene expression, that cooperate with transcriptional activation in providing rapid adaptive changes in response to many biological processes, including the activation of the immune response. The disregulation of this mechanism is increasingly recognized as a pathogenic event in diseases such as cancer and metabolic disorders. Increase in mRNA stability critically regulates the expression of several key genes in immunity and inflammation. We found that production of the CC chemokine eotaxin triggered by IL-4 and TNFa in human airway epithelial cells relies on the stabilization of the eotaxin mRNA, and that this process involves the cytokine-induced association of HuR to the 3'UTR of eotaxin mRNA. We gathered further data pointing at HuR as important mediator of posttranscriptional regulation of other relevant genes in allergy. On this basis, we hypothesize that the cytokine milieu at the site of chronic allergic inflammation could alter the proper and timely degradation of inflammatory transcripts by activating HuR, which mediate the aberrant stabilization of multiple transcripts and ultimately, the increased production of proinflammatory proteins. Overall, our research seeks to test the role of HuR in the pathogenesis of chronic allergic inflammation by answering three major questions: 1) what is the set of target mRNAs that HuR coordinately regulates in airway epithelial cells and T lymphocytes (Aim 1);2) what are the pathways by which inflammatory signals activate HuR-mediated function (Aim 2);3) what is the effect of modulating HuR function on inflammation and HuR target gene expression in a mouse model of inflammation (Aim 3). The studies proposed could uncover a role for HuR in coordinating the expression of a subset of relevant effectors of allergic inflammation, could reveal previously unrecognized signaling pathways governing the posttranscriptional regulation of these genes and ultimately identify HuR as a regulatory molecule whose local inhibition might be therapeutically desirable.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
3R01AI060990-05S1
Application #
7925184
Study Section
Lung Cellular, Molecular, and Immunobiology Study Section (LCMI)
Program Officer
Dong, Gang
Project Start
2009-09-22
Project End
2011-08-31
Budget Start
2009-09-22
Budget End
2011-08-31
Support Year
5
Fiscal Year
2009
Total Cost
$309,561
Indirect Cost
Name
Johns Hopkins University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Stellato, Cristiana; Gubin, Matthew M; Magee, Joseph D et al. (2011) Coordinate regulation of GATA-3 and Th2 cytokine gene expression by the RNA-binding protein HuR. J Immunol 187:441-9
Fan, Jinshui; Ishmael, Faoud T; Fang, Xi et al. (2011) Chemokine transcripts as targets of the RNA-binding protein HuR in human airway epithelium. J Immunol 186:2482-94
Ishmael, Faoud T; Fang, Xi; Houser, Kenneth R et al. (2011) The human glucocorticoid receptor as an RNA-binding protein: global analysis of glucocorticoid receptor-associated transcripts and identification of a target RNA motif. J Immunol 186:1189-98
Ishmael, Faoud T; Fang, Xi; Galdiero, Maria Rosaria et al. (2008) Role of the RNA-binding protein tristetraprolin in glucocorticoid-mediated gene regulation. J Immunol 180:8342-53
Casolaro, Vincenzo; Fang, Xi; Tancowny, Brian et al. (2008) Posttranscriptional regulation of IL-13 in T cells: role of the RNA-binding protein HuR. J Allergy Clin Immunol 121:853-9.e4
Stellato, Cristiana (2007) Glucocorticoid actions on airway epithelial responses in immunity: functional outcomes and molecular targets. J Allergy Clin Immunol 120:1247-63;quiz 1264-5
Fan, J; Heller, N M; Gorospe, M et al. (2005) The role of post-transcriptional regulation in chemokine gene expression in inflammation and allergy. Eur Respir J 26:933-47