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Chemoattraction of macrophages by secretory molecules derived from cells expressing the signal peptide of eosinophil cationic protein

Yu-Shu Liu1, Pei-Wen Tsai4, Yong Wang5, Tan-chi Fan6, Chia-Hung Hsieh2, Margaret Dah-Tsyr Chang47, Tun-Wen Pai8, Chien-Fu Huang9, Chung-Yu Lan4 and Hao-Teng Chang123*

Author Affiliations

1 Graduate Institute of Molecular Systems Biomedicine, College of Medicine, China Medical University, Taichung, Taiwan

2 Graduate Institute of Basic Medical Science, College of Medicine, China Medical University, Taichung, Taiwan

3 China Medical University Hospital, Taichung, Taiwan

4 Institute of Molecular and Cellular Biology, National Tsing Hua University, Hsinchu, Taiwan

5 Academy of Mathematics and Systems Science, Chinese Academy of Sciences, Beijing, China

6 Genomic Research Center, Academia Sinica, Taipei, Taiwan

7 Department of Medical Science, National Tsing Hua University, Hsinchu, Taiwan

8 Department of Computer Science and Engineering, National Taiwan Ocean University, Keelung, Taiwan

9 Department of Biological Science and Technology, I-Shou University, Kaohsiung, Taiwan

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BMC Systems Biology 2012, 6:105  doi:10.1186/1752-0509-6-105

Published: 20 August 2012



Eosinophil cationic protein is a clinical asthma biomarker that would be released into blood, especially gathered in bronchia. The signal peptide of eosinophil cationic protein (ECPsp) plays an important role in translocating ECP to the extracellular space. We previously reported that ECPsp inhibits microbial growth and regulates the expression of mammalian genes encoding tumor growth factor-α (TGF-α) and epidermal growth factor receptor (EGFR).


In the present study, we first generated a DNA microarray dataset, which showed that ECPsp upregulated 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 regulate cytokine expression and release, served as hubs to connect the pathways of cytokine stimulation (TGF-α and EGFR pathways) and inflammatory responses. Furthermore, integrating TGF-α and EGFR with the functional linkage network indicated that STAT1 and STAT2 served as hubs that connect 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.

Eosinophil cationic protein (ECP); Signal peptide; Inflammation; Functional linkage network; Cell migration