A distinct and unique transcriptional program expressed by tumor-associated macrophages (defective NF-κB and enhanced IRF-3/STAT1 activation)
A distinct and unique transcriptional program expressed by tumor-associated macrophages (defective NF-κB and enhanced IRF-3/STAT1 activation)
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DOI：
10.1182/blood-2005-01-0428
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发表时间：
2006-03-01
期刊：
影响因子：
20.3
通讯作者：
Sica, A
中科院分区：
文献类型：
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作者：
Biswas, SK;Gangi, L;Sica, A
为了确定肿瘤相关巨噬细胞（TAMs）功能的分子基础，我们采用cDNA微阵列技术，将从小鼠纤维肉瘤中分离的TAMs与腹膜巨噬细胞（佩奇）和骨髓抑制细胞（MSC）进行比较，以表征TAMs的基因表达谱。在差异表达基因中，15个与炎症和免疫相关的基因通过实时聚合酶链反应（PCR）和蛋白质生产进行了验证。静息TAM显示出特征性基因表达模式，如预期的那样，编码免疫抑制细胞因子IL-10、吞噬相关受体/分子（Msr 2和C1 q）和炎性趋化因子（CCL 2和CCL 5）的基因表达更高，以及出乎意料的IFN诱导型趋化因子（CXCL 9、CXCL 10、CXCL 16）。免疫组织学证实并扩展了体外分析，显示TAM表达M2相关分子（例如IL-10和MGL 1）以及CCL 2、CCL 5、CXCL 9、CXCL 10和CXCL 16，但无明显的NOS 2。脂多糖（LPS）介导的TAM活化导致几种促炎细胞因子（如IL-10、IL-6、TNF-α）和趋化因子（如CCL 3）表达缺陷，而免疫抑制细胞因子（IL-10、TGF β）和IFN诱导型趋化因子（CCL 5、CXCL 9、CXCL 10、CXCL 16）表达强烈上调。因此，对来自鼠肉瘤的TAM的分析揭示了与M2表型（IL-10（高），IL-12（低））相关的IFN诱导型趋化因子的意外表达，以及NF-κ B相对于IRF-3/STAT 1途径的趋化调节。
To identify the molecular basis underlying the functions of tumor-associated macrophages (TAMs), we characterized the gene expression profile of TAMs isolated from a murine fibrosarcoma in comparison with peritoneal macrophages (PECs) and myeloid suppressor cells (MSCs), using a cDNA microarray technology. Among the differentially expressed genes, 15 genes relevant to inflammation and immunity were validated by real-time polymerase chain reaction (PCR) and protein production. Resting TAMs showed a characteristic gene expression pattern with higher expression of genes coding for the immunosuppressive cytokine IL-10, phagocytosis-related receptors/molecules (Msr2 and C1q), and inflammatory chemokines (CCL2 and CCL5) as expected, as well as, unexpectedly, IFN-inducible chemokines (CXCL9, CXCL10, CXCL16). Immunohistology confirmed and extended the in vitro analysis by showing that TAMs express M2-associated molecules (eg, IL-10 and MGL1), as well as CCL2, CCL5, CXCL9, CXCL10, and CXCL16, but no appreciable NOS2. Lipopolysaccharide (LPS)-mediated activation of TAMs resulted in defective expression of several proinflammatory cytokines (eg, IL-10, IL-6, TNF-alpha) and chemolkines (eg, CCL3), as opposed to a strong up-regulation of immunosuppressive cytokines (IL-10, TGF beta) and IFN-inducible chemokines (CCL5, CXCL9, CXCL10, CXCL16). Thus, profiling of TAMs from a murine sarcoma revealed unexpected expression of IFN-inducible chemokines, associated with an M2 phenotype (IL-10(high), IL-12(low)), and divergent regulation of the NF-kappa B versus the IRF-3/STAT1 pathway.