Karpuzoglu Ebru, Ahmed S Ansar
Center for Molecular Medicine and Infectious Diseases, Department of Biomedical Sciences and Pathobiology, Virginia-Maryland Regional College of Vet. Med., Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, USA.
Nitric Oxide. 2006 Nov;15(3):177-86. doi: 10.1016/j.niox.2006.03.009. Epub 2006 May 2.
Nitric oxide plays a central role in the physiology and pathology of diverse tissues including the immune system. It is clear that the levels of nitric oxide must be carefully regulated to maintain homeostasis. Appropriate levels of nitric oxide derived from iNOS assist in mounting an effective defense against invading microbes. Conversely, inability to generate nitric oxide results in serious, even fatal, susceptibility to infections. Further, dysregulation or overproduction of nitric oxide has been implicated in the pathogenesis of many disorders, including atherosclerosis, neurodegenerative diseases, inflammatory autoimmune diseases, and cancer. Therefore, depending upon the levels of nitric oxide generated, the potential exists for nitric oxide to behave like a "double-edged" biological sword. Taking these issues into consideration, it is thus pivotal to understand the regulation of nitric oxide. Nitric oxide is regulated by many endogenous factors including hormones such as estrogens. While the effects of estrogen on the generation of nitric oxide in non-immune tissues are relatively well documented, the effect of estrogen on iNOS/nitric oxide in immune cells is only now becoming apparent. Our laboratory has recently shown that estrogen treatment of mice markedly upregulates the levels of iNOS mRNA, iNOS protein, and nitric oxide in activated splenocytes. This upregulation of nitric oxide is in part mediated through interferon-gamma (IFN-gamma), a pro-inflammatory cytokine that is enhanced by estrogen. These findings are important considering that estrogens are not only involved in regulation of normal immune responses, but also are implicated in many autoimmune and inflammatory diseases. To date, there are no reviews on the effects of estrogen on immune tissue-derived nitric oxide and therefore this review will address this critical gap in the literature. Given the increasing importance of immune-tissue-derived iNOS in health and disease, studies on estrogen-induced regulation of iNOS may offer a better understanding of diseases and aid in devising new therapeutic interventions.
一氧化氮在包括免疫系统在内的多种组织的生理和病理过程中起着核心作用。显然，一氧化氮的水平必须得到严格调控以维持体内平衡。诱导型一氧化氮合酶（iNOS）产生的适量一氧化氮有助于机体对入侵微生物发起有效的防御。相反，无法产生一氧化氮会导致对感染的严重甚至致命的易感性。此外，一氧化氮的失调或过量产生与许多疾病的发病机制有关，包括动脉粥样硬化、神经退行性疾病、炎症性自身免疫疾病和癌症。因此，根据一氧化氮的生成水平，一氧化氮有可能像一把“双刃剑”。考虑到这些问题，了解一氧化氮的调控机制至关重要。一氧化氮受到许多内源性因素的调控，包括雌激素等激素。虽然雌激素对非免疫组织中一氧化氮生成的影响已有相对充分的文献记载，但雌激素对免疫细胞中iNOS/一氧化氮的影响目前才逐渐显现。我们实验室最近发现，用雌激素处理小鼠可显著上调活化脾细胞中iNOS mRNA、iNOS蛋白和一氧化氮的水平。一氧化氮的这种上调部分是通过干扰素-γ（IFN-γ）介导的，IFN-γ是一种促炎细胞因子，其水平会因雌激素而升高。鉴于雌激素不仅参与正常免疫反应的调控，还与许多自身免疫和炎症性疾病有关，这些发现具有重要意义。迄今为止，尚无关于雌激素对免疫组织来源的一氧化氮影响的综述，因此本综述将填补这一重要的文献空白。鉴于免疫组织来源的iNOS在健康和疾病中的重要性日益增加，对雌激素诱导的iNOS调控的研究可能有助于更好地理解疾病，并有助于设计新的治疗干预措施。
