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Novel human neutrophil agonistic properties of arsenic trioxide: involvement of p38 mitogen‐activated protein kinase and/or c‐jun NH 2 ‐terminal MAPK but not extracellular signal‐regulated kinases‐1/2
Author(s) -
Binet François,
Girard Denis
Publication year - 2008
Publication title -
journal of leukocyte biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.819
H-Index - 191
eISSN - 1938-3673
pISSN - 0741-5400
DOI - 10.1189/jlb.0708421
Subject(s) - p38 mitogen activated protein kinases , arsenic trioxide , kinase , mapk/erk pathway , microbiology and biotechnology , biology , signal transduction , apoptosis , biochemistry
Arsenic trioxide (ATO) is known for treating acute promyelocytic leukemia and for inducing apoptosis and mitogen‐activated protein kinases (MAPKs) in promyelocytes and cancer cells. We recently reported that ATO induces neutrophil apoptosis. The aim of this study was to establish whether or not ATO recruits MAPKs in neutrophils, as well as to further investigate its agonistic properties. We found that ATO activates p38 and that, unlike H 2 O 2 , this response was not inhibited by exogenous catalase. Also, we demonstrated that ATO‐induced p38 activation occurs before H 2 O 2 generation and without a calcium burst. We next established that ATO recruits c‐jun NH 2 ‐terminal (JNK) but not extracellular signal‐regulated kinase 1 and 2 (Erk‐1/2). Using pharmacological inhibitors, we found that the proapoptotic activity of ATO occurs by a MAPK‐independent mechanism. In contrast, the ability of ATO to enhance adhesion, migration, phagocytosis, release, and activity of gelatinase and degranulation of secretory, specific, and gelatinase, but not azurophilic granules, is dependent upon activation of p38 and/or JNK. This is the first study establishing that ATO possesses important agonistic properties in human neutrophils. Given the central role of neutrophils in various inflammatory disorders, we propose that ATO might have broader therapeutic implications in clinics, especially for regulating inflammation.