Gpnmb is induced in macrophages by IFN-γ and lipopolysaccharide and acts as a feedback regulator of proinflammatory responses
Gpnmb is induced in macrophages by IFN-γ and lipopolysaccharide and acts as a feedback regulator of proinflammatory responses
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DOI：
10.4049/jimmunol.178.10.6557
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发表时间：
2007-05-15
影响因子：
4.4
通讯作者：
Hume, David A.
中科院分区：
文献类型：
--
作者：
Ripoll, Vera M.;Irvine, Katharine M.;Hume, David A.
炎症过程需要巨噬细胞谱系细胞中一组基因的选择性表达。为了确定炎症的候选调节因子，我们使用 cDNA 微阵列来比较炎症巨噬细胞（巯基乙酸引发的腹膜巨噬细胞）、骨髓源性巨噬细胞、非贴壁脾细胞和成纤维细胞的转录组。我们鉴定了巨噬细胞限制并在炎症巨噬细胞中进一步升高的基因，并表征了其中一个基因 gpnmb 的功能。 Gpnmb mRNA 表达在骨髓单核细胞系和巨噬细胞相关组织中富集，并在巨噬细胞分化过程中强烈上调。在 RAW264.7 细胞中表达的表位标记的 GPNMB 表现出核周分布，并与高尔基体标记外壳蛋白 β 共定位。在用 IFN-γ 和 LPS 激活巨噬细胞后，GPNMB 从高尔基体转移到分散到外围的囊泡区室。 RAW264.7 细胞中的 gpnmb 过表达导致 LPS 响应的细胞因子 IL-6 和 IL-12p40 以及炎症介质 NO 的产生减少 2 倍。 DBA 小鼠的 gpnmb 基因存在失活点突变，在 LPS 的作用下，骨髓细胞数量减少，巯基乙酸引发的腹腔巨噬细胞数量增加，促炎细胞因子水平升高。因此，GPNMB 充当巨噬细胞炎症反应的负调节因子。免疫学杂志，2007 年，178：6557-6566。
The process of inflammation requires the selective expression of a suite of genes in cells of the macrophage lineage. To identify candidate regulators of inflammation, we used cDNA microarrays to compare the transcriptome of inflammatory macrophages (thioglycolate-elicited peritoneal macrophages), bone marrow-derived macrophages, nonadherent spleen cells, and fibroblasts. We identified genes that were macrophage restricted and further elevated in inflammatory macrophages, and characterized the function of one such gene, gpnmb. Gpnmb mRNA expression was enriched in myelomonocytic cell lines and macrophage-related tissues and strongly up-regulated during macrophage differentiation. Epitope-tagged GPNMB expressed in RAW264.7 cells exhibited a perinuclear distribution and colocalized with the Golgi marker coat protein beta. Upon activation of macrophages with IFN-gamma and LPS, GPNMB translocated from the Golgi apparatus to vesicular compartments scattered toward the periphery. Gpnmb overexpression in RAW264.7 cells caused a 2-fold reduction in the production of the cytokines IL-6 and IL-12p40 and the inflammatory mediator NO in response to LPS. DBA mice, which have an inactivating point mutation in the gpnmb gene, exhibited reduced numbers of myeloid cells, elevated numbers of thioglycolate-elicited peritoneal macrophages, and higher levels of proinflammatory cytokines in response to LPS. Thus, GPNMB acts as a negative regulator of macrophage inflammatory responses. The Journal of Immunology, 2007, 178: 6557-6566.