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PI 3K, ERK , p38 MAPK and integrins regulate CCR 3‐mediated secretion of mouse and human eosinophil‐associated RN ases
Author(s) -
Shamri R.,
Young K. M.,
Weller P. F.
Publication year - 2013
Publication title -
allergy
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.363
H-Index - 173
eISSN - 1398-9995
pISSN - 0105-4538
DOI - 10.1111/all.12163
Subject(s) - ccl11 , secretion , eosinophil , microbiology and biotechnology , integrin , chemokine , biology , mapk/erk pathway , signal transduction , immunology , receptor , immune system , eotaxin , biochemistry , asthma
Background Eosinophils have the capacity to secrete varied cytotoxic proteins. Among the proteins are the eosinophil‐associated RN ases ( EAR s): the human eosinophil‐derived neurotoxin and eosinophilic cationic protein, and their murine ortholog EAR s, which have been shown to be involved in host defense, tissue remodeling, and immunity regulation. However, the signal transduction that regulates EAR s secretion in response to physiological stimuli, such as chemokines, has been little studied in human and scarcely in mouse eosinophils, the foremost animal model for eosinophil‐associated human diseases. Objective In this study, we aimed to understand the signal transduction involved in the secretion of enzymatically active EAR s following chemokine stimulation. Methods Fresh mouse and human eosinophils were stimulated with CCL 11 and CCL 24, and the secretion of enzymatically active EAR s was detected using an RN ase activity assay. The involvement of signaling factors or integrins was probed using specific inhibitors and blocking antibodies. Adhesion was evaluated by microscopy. Results We found that secretion of mouse EAR s in response to CCL 11 and CCL 24 was G αi ‐dependent. Both mouse and human eosinophils required the activation of PI 3 K , ERK , and p38 MAPK . In addition, the adhesion molecules β1 and β2 integrins were found to be crucial for EAR secretion, and we suggest a mechanism in which spreading is obligatory for EAR secretion. Conclusions Collectively, these data suggest a common CCR 3‐mediated signaling pathway that leads to EAR secretion in both mouse and human eosinophils. These findings are applicable for eosinophil‐mediated host defense and eosinophil‐associated diseases.