TY - JOUR
T1 - Human eosinophils are activated by cysteine proteases and release inflammatory mediators
AU - Miike, Satoshi
AU - Kita, Hirohito
N1 - Copyright:
Copyright 2017 Elsevier B.V., All rights reserved.
PY - 2003/4/1
Y1 - 2003/4/1
N2 - Background: Recent studies suggest that serine proteases are involved in various biological responses through activation of protease-activated receptors (PARs). However, the functions of other proteases, such as cysteine proteases, are poorly understood and need elucidation. Objective: We examined the effects of an authentic cysteine protease, papain, and a protease derived from the mite allergen, Der f 1, on functions of human eosinophils. Methods: Purified eosinophils were incubated with papain or Der f 1. Eosinophil activation was monitored by superoxide anion generation and by degranulation. Intracellular signaling pathways were investigated through use of pharmacologic approaches. Results: We found that papain potently induces human eosinophils to degranulate and to produce superoxide anion. A cysteine protease inhibitor, E-64, abolished the stimulatory effects of papain, which suggests that the protease activity of papain is necessary to trigger eosinophil responses. The eosinophil's response to papain was enhanced by IL-5 and mediated by activation of the phosphatidylinositol 3-kinase/Akt pathway. Interestingly, whereas a serine protease, trypsin, activated eosinophils through PAR2, the effects of papain were not inhibited by an antibody to PAR2, which suggests another novel mechanism for the eosinophils' response to cysteine proteases. It is likely that these observations are clinically important, because eosinophils were activated by a natural cysteine protease allergen, Der f 1, and released granule proteins. Conclusion: Human eosinophils are probably equipped with machineries that recognize and respond to cysteine proteases, such as those found at allergic inflammation sites; the result is active release of proinflammatory mediators.
AB - Background: Recent studies suggest that serine proteases are involved in various biological responses through activation of protease-activated receptors (PARs). However, the functions of other proteases, such as cysteine proteases, are poorly understood and need elucidation. Objective: We examined the effects of an authentic cysteine protease, papain, and a protease derived from the mite allergen, Der f 1, on functions of human eosinophils. Methods: Purified eosinophils were incubated with papain or Der f 1. Eosinophil activation was monitored by superoxide anion generation and by degranulation. Intracellular signaling pathways were investigated through use of pharmacologic approaches. Results: We found that papain potently induces human eosinophils to degranulate and to produce superoxide anion. A cysteine protease inhibitor, E-64, abolished the stimulatory effects of papain, which suggests that the protease activity of papain is necessary to trigger eosinophil responses. The eosinophil's response to papain was enhanced by IL-5 and mediated by activation of the phosphatidylinositol 3-kinase/Akt pathway. Interestingly, whereas a serine protease, trypsin, activated eosinophils through PAR2, the effects of papain were not inhibited by an antibody to PAR2, which suggests another novel mechanism for the eosinophils' response to cysteine proteases. It is likely that these observations are clinically important, because eosinophils were activated by a natural cysteine protease allergen, Der f 1, and released granule proteins. Conclusion: Human eosinophils are probably equipped with machineries that recognize and respond to cysteine proteases, such as those found at allergic inflammation sites; the result is active release of proinflammatory mediators.
KW - Allergy
KW - Eosinophils
KW - Inflammation
UR - http://www.scopus.com/inward/record.url?scp=0037391735&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0037391735&partnerID=8YFLogxK
U2 - 10.1067/mai.2003.1332
DO - 10.1067/mai.2003.1332
M3 - Article
C2 - 12704347
AN - SCOPUS:0037391735
SN - 0091-6749
VL - 111
SP - 704
EP - 713
JO - Journal of Allergy and Clinical Immunology
JF - Journal of Allergy and Clinical Immunology
IS - 4
ER -