Human eosinophils are activated by cysteine proteases and release inflammatory mediators

Satoshi Miike, Hirohito Kita

Research output: Contribution to journalArticle

77 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)704-713
Number of pages10
JournalJournal of Allergy and Clinical Immunology
Volume111
Issue number4
DOIs
StatePublished - Apr 1 2003

Fingerprint

Cysteine Proteases
Eosinophils
Papain
Peptide Hydrolases
Serine Proteases
Superoxides
Allergens
Proteinase-Activated Receptors
Phosphatidylinositol 3-Kinase
Cysteine Proteinase Inhibitors
Mites
Interleukin-5
Trypsin
Inflammation

Keywords

  • Allergy
  • Eosinophils
  • Inflammation

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Human eosinophils are activated by cysteine proteases and release inflammatory mediators. / Miike, Satoshi; Kita, Hirohito.

In: Journal of Allergy and Clinical Immunology, Vol. 111, No. 4, 01.04.2003, p. 704-713.

Research output: Contribution to journalArticle

@article{667ce374ce3149bd8e98717078ba87f8,
title = "Human eosinophils are activated by cysteine proteases and release inflammatory mediators",
abstract = "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.",
keywords = "Allergy, Eosinophils, Inflammation",
author = "Satoshi Miike and Hirohito Kita",
year = "2003",
month = "4",
day = "1",
doi = "10.1067/mai.2003.1332",
language = "English (US)",
volume = "111",
pages = "704--713",
journal = "Journal of Allergy and Clinical Immunology",
issn = "0091-6749",
publisher = "Mosby Inc.",
number = "4",

}

TY - JOUR

T1 - Human eosinophils are activated by cysteine proteases and release inflammatory mediators

AU - Miike, Satoshi

AU - Kita, Hirohito

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

VL - 111

SP - 704

EP - 713

JO - Journal of Allergy and Clinical Immunology

JF - Journal of Allergy and Clinical Immunology

SN - 0091-6749

IS - 4

ER -