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) de- lays 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 tran- scription 3 (STAT3). Here, we show that type I and type II interferons (IFNs), which bind to the dis- tinct 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 mecha- nism. 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 pro- tein, 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 anti- apoptotic effect on human neutrophils. J. Leukoc. Biol. 78: 301-309; 2005.