Expression of the inhibitor of apoptosis (IAP) family members in human neutrophils: up-regulation of cIAP2 by granulocyte colony-stimulating factor and overexpression of cIAP2 in chronic neutrophilic leukemia.
Human neutrophils were found to express members of the inhibitor of apoptosis (IAP) family, namely cellular IAP1 (cIAP1), cIAP2, and X-linked IAP. Among these members, cIAP2 expression was selectively up-regulated by stimulation with granulocyte colony-stimulating factor (G-CSF), but not with granulocyte-macrophage CSF. The increased expression of cIAP2 mRNA was detected as early as 30 minutes after in vitro stimulation with G-CSF, and the elevated level of cIAP2 protein was detected at 1 hour. The elevated level of cIAP2 protein was also detected in peripheral blood neutrophils obtained from healthy donors receiving G-CSF administration. G-CSF-induced up-regulation of cIAP2 mRNA and protein, phosphorylation of signal transducer and activator of transcription 3 (STAT3), and the antiapoptotic effects were inhibited by pretreatment of cells with AG490, a specific inhibitor of Janus kinase 2 (JAK2). Mature neutrophils from a patient with chronic neutrophilic leukemia exhibited remarkable overexpression of cIAP2 mRNA and prolongation of survival, whereas cIAP2 mRNA expression and survival in mature neutrophils from patients with chronic myelogenous leukemia were essentially similar to those in normal neutrophils. These findings suggest that cIAP2 expression is up-regulated by G-CSF through activation of the JAK2-STAT3 pathway, and increased expression of cIAP2 protein may contribute to G-CSF-mediated antiapoptosis. In addition, overexpression of cIAP2 may be partly responsible for sustained neutrophilia at least in some cases of chronic neutrophilic leukemia.
Hasegawa
Taro
T
Department of Physiology, Osaka City University Medical School, Japan.
Suzuki
Kenichi
K
Sakamoto
Chikahiko
C
Ohta
Kensuke
K
Nishiki
Saori
S
Hino
Masayuki
M
Tatsumi
Noriyuki
N
Kitagawa
Seiichi
S
D017209:Apoptosis / Q000187:drug effects; D016022:Case-Control Studies; D004268:DNA-Binding Proteins / Q000378:metabolism; D016179:Granulocyte Colony-Stimulating Factor / Q000008:administration & dosage / Q000494:pharmacology*; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D019476:Insect Proteins / Q000096:biosynthesis* / Q000235:genetics; D053614:Janus Kinase 2; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive; D015467:Leukemia, Neutrophilic, Chronic / Q000209:etiology / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009504:Neutrophils / Q000378:metabolism*; D014176:Protein Biosynthesis; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011506:Proteins / Q000235:genetics; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger / Q000096:biosynthesis; D050796:STAT3 Transcription Factor; D015534:Trans-Activators / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases; D015854:Up-Regulation / Q000187:drug effects
D004268:DNA-Binding Proteins; D051034:Inhibitor of Apoptosis Proteins; D019476:Insect Proteins; D011506:Proteins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D015534:Trans-Activators; D016179:Granulocyte Colony-Stimulating Factor; C494833:BIRC2 protein, human; D044767:Ubiquitin-Protein Ligases; D011505:Protein-Tyrosine Kinases; C507924:JAK2 protein, human; D053614:Janus Kinase 2