Kobayashi Scott D, Voyich Jovanka M, Braughton Kevin R, DeLeo Frank R
Laboratory of Human Bacterial Pathogenesis, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT 59840, USA.
J Immunol. 2003 Mar 15;170(6):3357-68. doi: 10.4049/jimmunol.170.6.3357.
Polymorphonuclear leukocytes (PMNs) are essential to innate immunity in humans and contribute significantly to inflammation. Although progress has been made, the molecular basis for termination of inflammation in humans is incompletely characterized. We used human oligonucleotide microarrays to identify genes encoding inflammatory mediators that were differentially regulated during the induction of apoptosis. One hundred thirty-three of 212 differentially expressed genes encoding proinflammatory factors, signal transduction mediators, adhesion molecules, and other proteins that facilitate the inflammatory response were down-regulated during the induction of apoptosis following PMN phagocytosis. Among these, 42 genes encoded proteins critical to the inflammatory response, including receptors for IL-8 beta, IL-10 alpha, IL-13 alpha 1, IL-15 alpha, IL-17, IL-18, C1q, low-density lipoprotein, IgG Fc (CD32), and formyl peptide, Toll-like receptor 6, platelet/endothelial cell adhesion molecule-1 (CD31), P-selectin (CD62), IL-1 alpha, IL-16, and granulocyte chemoattractant protein-2 were down-regulated. Many of these genes were similarly down-regulated during Fas-mediated or camptothecin-induced apoptosis. We used flow cytometry to confirm that IL-8R beta (CXCR2) and IL-1 alpha were significantly down-regulated during PMN apoptosis. We also discovered that 23 genes encoding phosphoinositide and calcium-mediated signal transduction components, which comprise complex pathways essential to the inflammatory response of host cells, were differentially regulated during PMN apoptosis. Importantly, our data demonstrate that PMNs down-regulate proinflammatory capacity at the level of gene expression during induction of apoptosis. These findings provide new insight into the molecular events that resolve inflammation following PMN activation in humans.
多形核白细胞（PMNs）对人类的先天免疫至关重要，并在炎症反应中发挥重要作用。尽管已取得进展，但人类炎症终止的分子基础仍未完全明确。我们使用人类寡核苷酸微阵列来鉴定在细胞凋亡诱导过程中差异调节的编码炎症介质的基因。在212个差异表达的编码促炎因子、信号转导介质、黏附分子和其他促进炎症反应的蛋白质的基因中，有133个在PMN吞噬后细胞凋亡诱导过程中被下调。其中，42个基因编码对炎症反应至关重要的蛋白质，包括IL-8β、IL-10α、IL-13α1、IL-15α、IL-17、IL-18、C1q、低密度脂蛋白、IgG Fc（CD32）和甲酰肽的受体、Toll样受体6、血小板/内皮细胞黏附分子-1（CD31）、P-选择素（CD62）、IL-1α、IL-16和粒细胞趋化蛋白-2均被下调。在Fas介导的或喜树碱诱导的细胞凋亡过程中，许多这些基因同样被下调。我们使用流式细胞术证实，在PMN细胞凋亡过程中，IL-8Rβ（CXCR2）和IL-1α显著下调。我们还发现，23个编码磷酸肌醇和钙介导的信号转导成分的基因在PMN细胞凋亡过程中差异调节，这些成分构成宿主细胞炎症反应所必需的复杂途径。重要的是，我们的数据表明，PMN在细胞凋亡诱导过程中在基因表达水平下调促炎能力。这些发现为人类PMN激活后解决炎症的分子事件提供了新的见解。
