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Mechanisms involved in interleukin‐15‐induced suppression of human neutrophil apoptosis: role of the anti‐apoptotic Mcl‐1 protein and several kinases including Janus kinase‐2, p38 mitogen‐activated protein kinase and extracellular signal‐regulated kinases‐1/2
Author(s) -
Pelletier Martin,
Ratthé Claude,
Girard Denis
Publication year - 2002
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/s0014-5793(02)03668-2
Subject(s) - janus kinase , microbiology and biotechnology , jak stat signaling pathway , p38 mitogen activated protein kinases , janus kinase 2 , mapk/erk pathway , ask1 , signal transduction , stat protein , biology , kinase , cancer research , mitogen activated protein kinase kinase , protein kinase a , chemistry , tyrosine kinase , stat3
Interleukin‐15 (IL‐15) is a pro‐inflammatory cytokine known as a general inhibitor of apoptosis, which possesses potential therapeutic properties. Although IL‐15 was previously found to be a human neutrophil agonist, its mode of action remains unknown. Herein, we were interested in elucidating the mechanisms by which it delays neutrophil apoptosis. IL‐15 was found to induce tyrosine phosphorylation events and to prevent loss of the anti‐apoptotic Mcl‐1 protein expression. Using different signal transduction inhibitors, we found that Janus kinase (Jak)‐2, Jak‐3, p38 mitogen‐activated protein kinase (MAPK) and extracellular signal‐regulated kinase (ERK), but not G proteins, are involved in IL‐15‐induced suppression of apoptosis. Furthermore, we found that IL‐15 activates Jak‐2, p38 MAPK and ERK‐1/2, but, unlike granulocyte macrophage‐colony‐stimulating factor (GM‐CSF), it does not activate signal transducer and activator of transcription (STAT)‐5a/b. We conclude that IL‐15 delays neutrophil apoptosis via several pathways, and that Mcl‐1 and several kinases contribute to this. We also conclude that, unlike GM‐CSF, IL‐15 does not activate the Jak‐2/STAT‐5 pathway found to be important in neutrophil signaling.