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Published online before print April 21, 2005

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(Journal of Leukocyte Biology. 2005;78:301-309.)
© 2005 by Society for Leukocyte Biology

Type I and type II interferons delay human neutrophil apoptosis via activation of STAT3 and up-regulation of cellular inhibitor of apoptosis 2

Erina Sakamoto^*, Fumihiko Hato^*, Takayuki Kato^*, Chikahiko Sakamoto^*, Mika Akahori^*, Masayuki Hino and Seiichi Kitagawa^*,1

^* Departments of Physiology and
Clinical Hematology, Osaka City University Graduate School of Medicine, Japan

¹ Correspondence: Department of Physiology, Osaka City University Graduate School of Medicine, Asahi-machi, Abeno-ku, Osaka 545-8585, Japan. E-mail: kitagawas{at}med.osaka-cu.ac.jp

We have recently demonstrated that granulocyte-colony stimulating factor (G-CSF) delays human neutrophil apoptosis via up-regulation of cellular inhibitor of apoptosis 2 (cIAP2), which is dependent on activation of Janus kinase 2 (JAK2) and signal transducer and activator of transcription 3 (STAT3). Here, we show that type I and type II interferons (IFNs), which bind to the distinct receptors, exert the antiapoptotic effect on human neutrophils through the similar mechanism. IFN- (type I IFN) and IFN- (type II IFN), like G-CSF, delayed human neutrophil apoptosis through the protein synthesis-dependent mechanism. Stimulation of neutrophils with IFN- or IFN- resulted in tyrosine phosphorylation of STAT1 and STAT3 but not phosphorylation of STAT5, Akt, extracellular signal-regulated kinase, and p38 mitogen-activated protein kinase. IFN- and IFN- induced the expression of transcripts of cIAP2 and suppressor of cytokine signaling 1 and 3, but not cIAP1, Mcl-1, and A1. IFN-- and IFN--induced up-regulation of cIAP2 mRNA and protein, phosphorylation of STAT3, and antiapoptotic effect were inhibited significantly by pretreatment of cells with AG490, a specific inhibitor of JAK2. These findings suggest that cIAP2 expression is up-regulated by IFN- and IFN- through, at least in part, activation of the JAK2-STAT3 pathway, and increased expression of the cIAP2 protein may contribute to an IFN-- and IFN--mediated antiapoptotic effect on human neutrophils.

Key Words: signal transducer and activator of transcription 3 • AG490 • granulocyte-colony stimulating factor

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