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- Mechanisms of Cytokine-induced Chemokine Responses in Respiratory Epithelium
- Mechanisms of Posttranscriptional Gene Regulation by Glucocorticoids (GC)
- Characterization of Chemokine-driven Epithelial Responses
My work over the past ten years has contributed to establish the notion that epithelial cells are a very important source of C-C chemokines, which are potent and selective chemoattractant and activating molecules for eosinophils, basophils and Th2 cells, and that epithelial-derived chemokines are important targets of GC inhibition 1-3. We found that both cytokine-induced upregulation and GC-mediated inhibition of eotaxin/CCL11 gene appeared to be critically mediated by changes in eotaxin mRNA stability4,5.
Recently, we identified the RNA-binding protein HuR as mediator of the cytokine-induced mRNA-stabilizing effect 4. HuR associates with the adenylate-uridylate-rich elements (ARE) present in the 3’untranslated (UTR) of mRNA molecules, and uniquely promotes mRNA stability and translation of numerous inflammatory genes.
We are presently funded to understand the impact of posttranscriptional regulation - and its molecular mechanisms - in cytokine-induced expression and GC-mediated modulation of epithelial-derived genes, in particular of chemokines. Posttranscriptional gene regulation – that is, regulation of mRNA transport, turnover and translation - is a powerful adaptive mechanism implemented by eukaryotic cells in response to a variety of cell perturbations such as stress, proliferation or immune activation and the deregulation of this mechanism, which is increasingly recognized as a pathogenic event in diseases such as cancer and metabolic disorders, is poorly characterized in the pathogenesis of allergic diseases. Additionally, very little is known on the extent and the mechanisms of posttranscriptional regulation in GC-mediated control of inflammatory gene expression 6.
In other studies similarly focused on chemokine biology in airway epithelium, we discovered that epithelial cells bear functional chemokine receptors, such as CCR3 7, indicating that these cells express a ‘chemokine network’ with potential autoregulatory functions. We are currently investigating the effects of chemokines on different functions of epithelial cells, such as inflammatory gene expression and wound healing.
Our ultimate goal is to increase the current knowledge on the role of chemokines in airway inflammation. By uncovering novel chemokine-driven functions as well as identifying regulatory pathways of their expression, we aim at discovering new targets of therapeutic intervention that would yield strong anti-inflammatory effects.
- Cristiana Stellato, M.D., Ph.D., Assistant Professor of Medicine - Principal Investigator
- Stephanie Curry, M.S., Senior Laboratory Technician
Ms. Curry conducts experimental work using different cellular and molecular biology tools and oversees all the different aspects of the laboratory including ordering, training postdoctoral fellows and students, etc.
- Jinshui Fan, M.D., Ph.D., Post-doctoral Fellow
Dr. Fan is an expert in mRNA turnover and has extensive training in molecular techniques for the study of posttranscriptional gene regulation in eukaryotic cells.
1. Stellato C, Beck LA, Gorgone GA, Proud D, Schall TJ, Ono SJ, Lichtenstein LM, Schleimer RP. Expression of the chemokine RANTES by a human bronchial epithelial cell line. Modulation by cytokines and glucocorticoids. J Immunol. 1995;155:410-418
2. Stellato C, Collins P, Ponath PD, Soler D, Newman W, La Rosa G, Li H, White J, Schwiebert LM, Bickel C, Liu M, Bochner BS, Williams T, Schleimer RP. Production of the novel C-C chemokine MCP-4 by airway cells and comparison of its biological activity to other C-C chemokines. J Clin Invest. 1997;99:926-936
3. Stellato C, Matsukura S, Fal A, White J, Beck LA, Proud D, Schleimer RP. Differential regulation of epithelial-derived C-C chemokine expression by IL-4 and the glucocorticoid budesonide. J Immunol. 1999;163:5624-5632
4. Atasoy U, Curry SL, López de Silanes I, Shyu AB, Casolaro V, Gorospe M, Stellato C. Regulation of Eotaxin Gene Expression by TNF and IL-4 Through Messenger RNA Stabilization: Involvement of the RNA-binding protein HuR. J Immunol. 2003;171:4369-4378
5. Heller NM, Curry S, Nickel R, Plunkett B, Huang S, Shyu A-B, Schleimer RP, Stellato C. Post-transcriptional regulation of eotaxin by glucocorticoids (GC) and by Interleukin (IL)-4. J Allergy Clin Immunol. 2002;109:S159
6. Stellato C. Post-transcriptional and nongenomic effects of glucocorticoids. Proceedings of the American Thoracic Society. 2004;1:255-263
7. Stellato C, Brummet ME, Plitt JR, Shahabuddin S, Baroody FM, Liu MC, Ponath PD, Beck LA. Expression of the C-C chemokine receptor CCR3 in human airway epithelial cells. J Immunol. 2001;166:1457-1461