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.
