Differential signaling mechanisms of HNP-induced IL-8 production in human lung epithelial cells and monocytes
Differential signaling mechanisms of HNP-induced IL-8 production in human lung epithelial cells and monocytes
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DOI：
10.1002/jcp.21279
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发表时间：
2008-03-01
影响因子：
5.6
通讯作者：
Zhang, Haibo
中科院分区：
文献类型：
--
作者：
Syeda, Farisa;Liu, Hui-Yu;Zhang, Haibo
人中性粒细胞多肽(HNP)杀死微生物，但也通过激活核苷酸P2Y(6)受体上调趋化因子IL-8来调节免疫反应。然而，细胞内信号转导机制尚不清楚。人肺上皮细胞(A549)和单核细胞(U937)在没有和存在Src、细胞外信号调节激酶-1和2(ERK1/2)、p38丝裂原活化蛋白激酶(MAPK)、c-Jun-N末端激酶(JNK)和Akt特异性激酶抑制剂的情况下被HNP刺激。在检测的10种细胞因子中，HNP诱导了两种类型细胞中与IL-8的剂量依赖和选择性产生相关的快速磷酸化。在两种细胞中，HNP诱导的IL-8产生均可被Src酪氨酸激酶抑制剂PP2、MEK 1/2抑制剂U0126和磷脂酰肌醇3激酶(PI3K)抑制剂LY294002阻断，但不能被JNK抑制剂SP600125阻断。P38抑制剂SB203580仅抑制HNP诱导的单核细胞IL-8的产生。阻断Src激酶可钝化HNP诱导的单核细胞ERK1/2和Akt的磷酸化，但不影响p38。相反，抑制Src对肺上皮细胞中其他蛋白的磷酸化没有影响。我们的结论是，在HNP诱导的IL-8释放中，ERK 1/2和PI3K/Akt通路的激活是必需的，这种释放在肺上皮细胞中以不依赖于Src的方式发生，而在单核细胞中则是依赖于Src的。
Human neutrophil peptides (HNP) kill microorganisms but also modulate immune responses through upregulation of the chemokine IL-8 by activation of the nucleotide P2Y(6) receptor. However, the intracellular signaling mechanisms remain yet to be determined. Human lung epithelial cells (A549) and monocytes (U937) were stimulated with HNP in the absence and presence of the specific kinase inhibitors for Src, extracellular signal-regulated kinase-1 and -2 (ERK1/2), p38 mitogen-activated protein kinase (MAPK), c-Jun-N-terminal kinases (JNK), and Akt. HNP induced a rapid phosphorylation of the kinases in both cell types associated with a dose-dependent, selective production of IL-8 among 10 cytokines assayed. The HNP-induced IL-8 production was blocked by the Src tyrosine kinase inhibitor PP2, MEK 1/2 inhibitor U0126, and the phosphatidylinositol 3 kinase (PI3K) inhibitor LY294002, but not by the JNK inhibitor SP600125 in both cell types. Treatment with the p38 inhibitor SB203580 attenuated the HNP-induced IL-8 production only in monocytes. Blockade of Src kinase blunted HNP-induced phosphorylation of the ERK 1/2 and Akt but not p38 in monocytes. In contrast, Src inhibition had no effect on phosphorylation of the other kinases in the lung epithelial cells. We conclude that the activation of ERK 1/2 and PI3K/Akt pathways is required for HNP-induced IL-8 release which occurs in a Src-independent manner in lung epithelial cells, while is Src-dependent in monocytes.