Molecular mechanisms underlying the synergistic induction of CXCL10 by LPS and IFN-γ in human neutrophils
Molecular mechanisms underlying the synergistic induction of CXCL10 by LPS and IFN-γ in human neutrophils
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DOI：
10.1002/eji.200737340
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发表时间：
2007-09-01
影响因子：
5.4
通讯作者：
Cassatella, Marco A.
中科院分区：
文献类型：
--
作者：
Tamassia, Nicola;Calzetti, Federica;Cassatella, Marco A.
CXCL10趋化因子是激活的Th1和NK细胞募集到炎症部位的关键趋化因子。CXCL10通常由骨髓细胞响应ifn - γ产生，也可由中性粒细胞产生，尽管后者需要ifn - γ和LPS的共同刺激。在这项研究中，我们研究了ifn - γ和TLR4连接协同诱导中性粒细胞中CXCL10表达的分子机制。通过初级转录real-time PCR分析，我们证明了CXCL10基因在中性粒细胞中被LPS + ifn - γ联合诱导转录，这与先前的研究一致，表明CXCL10基因表达增加并不反映mRNA稳定性增强。ifn诱导的STAT1。中性粒细胞暴露于这两种刺激时，活化和脂多糖（LPS）诱导的nf - κ B活化均未增强，而单核细胞中两种转录因子均被ifn - γ或LPS激活。最后，NF-kappa B的药理学抑制剂证明了其在中性粒细胞中通过LPS + ifn - γ以及单核细胞中通过LPS或ifn - γ诱导CXCL10表达中的作用。综上所述，这些结果表明，在中性粒细胞中，LPS和IFN-gamma对CXCL10基因表达的协同作用可能反映了LPS和IFN-gamma分别对NF-kappa B和STAT1转录因子的协同诱导。
The CXCL10 chemokine is a critical chemoattractant for the recruitment of activated Th1 and NK cells into inflammatory sites. CXCL10 is typically produced by myeloid cells in response to IFN-gamma, as well as by neutrophils, though the latter require a costimulation with IFN-gamma and LPS. In this study, we investigated the molecular mechanism(s) whereby IFN-gamma and TLR4 ligation synergize to induce CXCL10 expression in neutrophils. By primary transcript real-time PCR analysis, we demonstrate that the CXCL10 gene is transcriptionally induced by the LPS plus IFN-gamma combination in neutrophils, consistent with previous studies showing that increased CXCL10 gene expression does not reflect enhanced mRNA stability. The IFN-gamma-induced STAT1. activation and the lipopolysaccharide (LPS)-induced NF-kappa B activation were not enhanced if neutrophils were exposed to both stimuli, whereas both transcription factors were activated by IFN-gamma or LPS in monocytes. Finally, pharmacological inhibitors of NF-kappa B demonstrated its role in the induction of CXCL10 expression by LPS plus IFN-gamma in neutrophils, and by LPS or IFN-gamma in monocytes. Together, these results suggest that in neutrophils, the synergy observed between LPS and IFN-gamma toward CXCL10 gene expression likely reflects the cooperative induction of the NF-kappa B and STAT1 transcription factors by LPS and IFN-gamma, respectively.