NAD(P)H oxidase 1, a product of differentiated colon epithelial cells, can partially replace glycoprotein 91phox in the regulated production of superoxide by phagocytes
NAD(P)H oxidase 1, a product of differentiated colon epithelial cells, can partially replace glycoprotein 91phox in the regulated production of superoxide by phagocytes
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DOI：
10.4049/jimmunol.171.1.299
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发表时间：
2003-07-01
影响因子：
4.4
通讯作者：
Leto, TL
中科院分区：
文献类型：
--
作者：
Geiszt, M;Lekstrom, K;Leto, TL
活性氧 (ROS) 具有多种生理功能；在某些情况下，它们在宿主防御中发挥作用，而在其他情况下，它们在细胞信号传导或生物合成反应中发挥作用。我们研究了最近描述的 ROS 来源、NAD(P)H 氧化酶 1 或 Nox1 的表达和功能，它们与细胞增殖有关。小鼠结肠的原位杂交显示，在结肠隐窝的下三分之二内，Nox1 表达较高，上皮细胞在此进行增殖和分化。人类多肿瘤组织阵列分析证实了结肠特异性 Nox1 表达，主要在分化的上皮肿瘤中。用 1α,25-二羟基维生素 D-3 或 IFN-γ 分化 Caco2 和 HT29 细胞会增强 Nox1 表达并降低细胞增殖，表明 Nox1 在结肠上皮细胞中不起促有丝分裂氧化酶的作用。用编码Nox1的逆转录病毒转导可恢复gp91(phox)缺陷的PLB-985细胞中的激活和分化依赖性超氧化物产生，表明与吞噬细胞氧化酶(phox)的功能密切相似。此外，胞质成分 p47(phox) 和 p67(phox) 的共表达增强了重建 K562 细胞中的 Nox1 活性。最后，Nox1部分恢复了中性粒细胞中超氧化物的产生，这些中性粒细胞是从来自X连锁慢性肉芽肿病患者的gp91(phox)缺陷的CD34(+)外周血干细胞离体分化而来的。这些研究表明，Nox1 与其最接近的同源物 gp91(phox) 之间存在显着的功能同源性（辅因子依赖性和激活调节的超氧化物产生），表明吞噬细胞中 Nox1 表达的靶向上调可以为慢性肉芽肿性疾病的分子治疗提供一种新方法。
Reactive oxygen species (ROS) serve several physiological functions; in some settings they act in host defense, while in others they function in cellular signaling or in biosynthetic reactions. We studied the expression and function of a recently described source of ROS, NAD(P)H oxidase 1 or Nox1, which has been associated with cell proliferation. In situ hybridization in mouse colon revealed high Nox1 expression within the lower two-thirds of colon crypts, where epithelial cells undergo proliferation and differentiation. Human multitumor tissue array analysis confirmed colon-specific Nox1 expression, predominantly in differentiated epithelial tumors. Differentiation of Caco2 and HT29 cells with 1alpha,25-dihydroxyvitamin D-3 or IFN-gamma enhances Nox1 expression and decreases cell proliferation, suggesting that Nox1 does not function as a mitogenic oxidase in colon epithelial cells. Transduction with retrovirus encoding Nox1 restored activation and differentiation-dependent superoxide production in gp91(phox)-deficient PLB-985 cells, indicating close functional similarities to the phagocyte oxidase (phox). Furthermore, coexpression of cytosolic components, p47(phox) and p67(phox) , augments Nox1 activity in reconstituted K562 cells. Finally, Nox1 partially restores superoxide production in neutrophils differentiating ex vivo from gp91(phox)-deficient CD34(+) peripheral blood-derived stem cells derived from patients with X-linked chronic granulomatous disease. These studies demonstrate a significant functional homology (cofactor-dependent and activation-regulated superoxide production) between Nox1 and its closest homologue, gp91(phox), suggesting that targeted up-regulation of Nox1 expression in phagocytic cells could provide a novel approach in the molecular treatment of chronic granulomatous disease.