Translational Regulation in Bronchial Epithelial Cells

University Of Texas Hlth Sci Ctr Houston, Houston TX

Investigators

Abstract

Epithelial cells of the bronchial airways are directly exposed to the environment and are the first line of defense against airborne particulate matter, allergens and infectious agents. During allergic airway inflammation the epithelium is both a source of mediator production as well as a target of remodeling processes. Thus, bronchial epithelial cells play a critical role not only in the maintenance of physico-chemical homoeostasis of the airways but also in the pathogenesis of airway diseases. Yet, little is known about the post-transcriptional regulation of mediator, effector and remodeling gene expression in these cells during the inflammatory response. Using two in vitro cell models and an in vivo mouse model for allergic airway inflammation, our preliminary studies support the following model: Upon IL-4/TNF-αstimulation, transcriptional activation results in an influx of inflammatory mediator mRNAs into the cytoplasm, where microRNA (miRNA)-mediated translation repression is released, global translation increases, and P-bodies (cytoplasmic domains for storage and/or degradation of translationally repressed mRNAs) disassembled. These concerted post-transcriptional activities help the cell deal with a rapid demand for translating inflammatory mediator mRNAs into proteins. After a persistent exposure to IL-4/TNF-α, translocation of HuR, an AU-rich element (ARE) binding protein, from the nucleus to the cytoplasm is elicited in activated bronchial epithelial cells. HuR then associates with cytoplasmic ARE-containing mRNAs coding for inflammatory mediators to down-regulate their translation, thereby dampening the inflammatory response. The following specific aims are designed to test this model: 1) To elucidate the molecular and biochemical mechanisms that alter the function of miR-155, an miRNA closely linked to immunity, in activated bronchial epithelial cells and to define the role of miR-155 in regulating inflammatory mediator gene expression in bronchial epithelial cells;2) To determine whether a reduction in P-bodies is a hallmark of activated bronchial epithelial cells and how alteration of P-body assembly and disassembly influences the inflammatory responses in bronchial epithelial cells;and 3) To determine how HuR down-regulates the expression of inflammatory mediator molecules such as MCP-1 in activated bronchial epithelial cells and how altering HuR expression in bronchial epithelium modulates allergic airway inflammation. The proposed studies will provide important mechanistic insights into the post-transcriptional mechanisms operating in bronchial epithelial cells to regulate their inflammatory responses, thereby leading to the development of new therapeutic approaches to alleviate airway inflammation associated with chronic airway diseases such as asthma and chronic obstructive pulmonary diseases (COPD).