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

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-α (type I IFN) and IFN-γ (type II IFN), like G-CSF, delayed human neutrophil apoptosis through the protein synthesis-dependent mechanism. Stimulation of neutrophils with IFN-α or IFN-γ 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-α and IFN-γ induced the expression of transcripts of cIAP2 and suppressor of cytokine signaling 1 and 3, but not cIAP1, Mcl-1, and A1. IFN-α- and IFN-γ-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-α and IFN-γ through, at least in part, activation of the JAK2-STAT3 pathway, and increased expression of the cIAP2 protein may contribute to an IFN-α- and IFN-γ-mediated antiapoptotic effect on human neutrophils.