Type I and type II interferons delay human neutrophil apoptosis via activation of STAT3 and up-regulation of cellular inhibitor of apoptosis 2
Type I and type II interferons delay human neutrophil apoptosis via activation of STAT3 and up-regulation of cellular inhibitor of apoptosis 2
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DOI：
10.1189/jlb.1104690
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发表时间：
2005-07-01
影响因子：
5.5
通讯作者：
Kitagawa, S
中科院分区：
文献类型：
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作者：
Sakamoto, E;Hato, F;Kitagawa, S
我们最近证明，粒细胞集落刺激因子（G-CSF）通过上调细胞凋亡抑制剂2 （cIAP2）来延缓人中性粒细胞的凋亡，而细胞凋亡抑制剂2依赖于Janus激酶2 （JAK2）和信号转导和转录激活因子3 （STAT3）的激活。在这里，我们发现I型和II型干扰素（ifn）结合不同的受体，通过类似的机制对人中性粒细胞发挥抗凋亡作用。IFN- α （I型IFN）和IFN- γ （II型IFN）与G-CSF一样，通过蛋白质合成依赖机制延迟人中性粒细胞凋亡。ifn - α或ifn - γ刺激中性粒细胞可导致STAT1和STAT3酪氨酸磷酸化，但不会导致STAT5、Akt、细胞外信号调节激酶和p38丝裂原活化蛋白激酶磷酸化。ifn - α和ifn - γ诱导cIAP2转录本和细胞因子信号通路抑制因子I和3的表达，但不诱导cIAP1、Mc1-1和A1的表达。用JAK2特异性抑制剂AG490预处理细胞，可显著抑制ifn - α和ifn - γ诱导的cIAP2 mRNA和蛋白上调、STAT3磷酸化和抗凋亡作用。这些发现表明，至少部分通过激活JAK2-STAT3通路，ifn - α和ifn - γ上调cIAP2的表达，并且cIAP2蛋白表达的增加可能有助于ifn - α和ifn - γ介导的对人中性粒细胞的抗凋亡作用。
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-alpha (type I IFN) and IFN-gamma (type II IFN), like G-CSF, delayed human neutrophil apoptosis through the protein synthesis-dependent mechanism. Stimulation of neutrophils with IFN-alpha or IFN-gamma 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-alpha and IFN-gamma induced the expression of transcripts of cIAP2 and suppressor of cytokine signaling I and 3, but not cIAP1, Mc1-1, and A1. IFN-alpha- and IFN-gamma-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-alpha and IFN-gamma through, at least in part, activation of the JAK2-STAT3 pathway, and increased expression of the cIAP2 protein may contribute to an IFN-alpha- and IFN-gamma-mediated antiapoptotic effect on human neutrophils.