Chemoattraction of macrophages by secretory molecules derived from cells expressing the signal peptide of eosinophil cationic protein
| Autor: | Yu-Shu Liu, 劉雨書 |
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| Rok vydání: | 2012 |
| Druh dokumentu: | 學位論文 ; thesis |
| Popis: | 100 Eosinophil cationic protein (ECP) is a clinical asthma biomarker be released into blood, especially gathered in bronchia. The signal peptide of ECP (ECPsp) is known to play an important role in translocating ECP to extracellular space. However, it ECPsp also has novel functions of inhibiting microbial growth and regulating gene expression of tumor growth factor-alpha (TGF-a) and epidermal growth factor receptor (EGFR) in mammalian cells. In the present study, we first generated a DNA microarray dataset, which showed that ECPsp up-regulated proinflammatory molecules including chemokines, interferon-induced molecules, and Toll-like receptors. The levels of mRNAs encoding CCL5, CXCL10, CXCL11, CXCL16, STAT1 and STAT2 were increased in the presence of ECPsp by 2.07-, 4.21-, 7.52-, 2.6-, 3.58- and 1.67-fold, respectively. We then constructed a functional linkage network by integrating the microarray dataset with the pathway database of Kyoto Encyclopedia of Genes and Genomes (KEGG). Follow-up analysis revealed that STAT1 and STAT2, important transcriptional factors that regulates cytokine expression and release, served as a hub to connect the pathways of cytokine stimulation (TGF-a and EGFR pathways) and inflammatory responses. Furthermore, integrating TGF-?? and EGFR with the functional linkage network indicated that STAT1 served as a hubs that connects two functional clusters, including (1) cell proliferation and survival, and (2) inflammation. Finally, we found that conditioned medium in which cells that express ECPsp had been cultured could chemoattract macrophages. Experimentally, we also demonstrated that the migration of macrophage could be inhibited by the individual treatment of siRNAs of STAT1 or STAT2. Therefore, we hypothesize that ECPsp may function as a regulator for enhancing the migration of macrophages through the upregualtion of the transcriptional factors STAT1 and STAT2. The increased expression and release of various cytokines triggered by ECPsp may attract macrophages to bronchia to purge damaged cells. Our approach, involving experimental and computational systems biology, predicts pathways and potential biological functions for further characterization of this novel function of ECPsp under inflammatory conditions. |
| Databáze: | Networked Digital Library of Theses & Dissertations |
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