Suppression of thymic lymphomas and increased nonthymic lymphomagenesis in Trp53‐deficient mice lacking inducible nitric oxide synthase gene
Suppression of thymic lymphomas and increased nonthymic lymphomagenesis in Trp53‐deficient mice lacking inducible nitric oxide synthase gene
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缺乏诱导型一氧化氮合酶基因的 Trp53 缺陷小鼠胸腺淋巴瘤的抑制和非胸腺淋巴瘤发生的增加
DOI：
10.1002/ijc.20350
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发表时间：
2004
影响因子：
6.4
通讯作者：
H. Ohshima
中科院分区：
文献类型：
--
作者：
M. Tatemichi;H. Tazawa;M. Masuda;M. Saleem;S. Wada;L. Donehower;H. Ohgaki;H. Ohshima
Trp 53缺陷小鼠自发发生淋巴瘤，主要是胸腺起源，尽管分子机制在很大程度上仍然未知。由于已经报道了p53和iNOS之间的几种相互作用效应，我们假设胸腺中的iNOS活性与Trp 53缺陷小鼠的淋巴瘤发生有因果关系。因此，我们创建了具有Trp 53和iNOS基因的不同组合的小鼠品系。Western blot和组织学分析表明，iNOS蛋白在胸腺中的组成性表达独立于Trp 53状态，并且其表达在Trp 53 +/-和Trp 53-/-小鼠中比在Trp 53 +/+小鼠中增强。与相应的iNOS野生型小鼠相比，纯合型iNOS破坏使Trp 53-/-和Trp 53 +/-小鼠中胸腺淋巴瘤的发生率分别降低了近40%（p = 0.087）和90%（p < 0.05），但显著（p < 0.05）增加了Trp 53-/-和Trp 53 +/-小鼠中非胸腺淋巴瘤的发生。虽然iNOS基因破坏不影响胸腺淋巴瘤的表型，但iNOS基因的缺失使非胸腺淋巴瘤的谱系从B细胞转移到T细胞谱系。RT-PCR分析显示IL-10的表达增强，即使没有任何刺激，在具有Trp 53-/-iNOS-/-和Trp 53 +/-iNOS-/-基因组合但不是Trp 53-/-iNOS+/+或Trp 53 +/-iNOS+/+的衰老小鼠的脾脏中，IL-10的表达也可以对淋巴瘤发生具有促进作用。这些结果表明，iNOS可以增加Trp 53缺陷小鼠胸腺淋巴瘤的发展。虽然诱导型一氧化氮合酶可能对非胸腺淋巴瘤发生具有保护作用，但诱导型一氧化氮合酶对细胞因子产生的调节可能参与外周淋巴器官中抗淋巴瘤发生作用的潜在机制。© 2004 Wiley利斯公司
Trp53‐deficient mice spontaneously develop lymphomas, mainly of thymic origin, although the molecular mechanism remains largely unknown. As several interaction effects between p53 and iNOS have been reported, we hypothesized that iNOS activity in the thymus is causally linked to lymphomagenesis in Trp53‐deficient mice. We therefore created mouse strains with different combinations of the Trp53 and iNOS genes. Western blot and histologic analyses showed that the iNOS protein was constitutively expressed in the thymus independently of Trp53 status and its expression was enhanced in Trp53+/– and Trp53–/– mice compared to Trp53+/+ mice. Homozygous disruption of iNOS decreased the incidence of thymic lymphomas by almost 40% (p = 0.087) and 90% (p < 0.05) in Trp53–/– and Trp53+/– mice, respectively, compared to the respective iNOS wild‐type mice but significantly (p < 0.05) increased the development of nonthymic lymphomas in Trp53–/– and Trp53+/– mice. Although iNOS gene disruption did not affect the phenotype of thymic lymphomas, absence of the iNOS gene shifted the spectrum of nonthymic lymphoma from the B‐cell to the T‐cell lineage. RT‐PCR analysis revealed enhanced expression of IL‐10, which could have a promoting effect on lymphomagenesis, even without any stimulation, in the spleen of aging mice with the gene combinations Trp53–/–iNOS–/– and Trp53+/–iNOS–/– but not Trp53–/–iNOS+/+ or Trp53+/–iNOS+/+. These results suggest that iNOS could increase the development of thymic lymphomas in Trp53‐deficient mice. While iNOS may have protective effects against nonthymic lymphomagenesis, the regulation of cytokine production by iNOS may be involved in the underlying mechanism of antilymphomagenesis effects in the peripheral lymphoid organ. © 2004 Wiley‐Liss, Inc.