生物谷报道：美国Weill康奈尔医学院的一个研究组鉴定出两个基因对产生一种免疫系统细胞激素IL-10（白介素－10）至关重要。研究的结果发表在12月的Immunity杂志上。这项研究的首席研究人员是华人科学家马小京教授。参与这项研究的还有Weill康奈尔的刘建国（Jianguo Liu，音译）博士、Elain Y. Chung。
这一发现填补了与从红斑狼疮和I型糖尿病到癌症和艾滋病的一系列疾病相关的一个生物化学途径的一个重要的“迷失链条”。
IL-10是一种重要的抗炎性细胞因子,近年发现在树突状细胞的免疫调控中具有重要作用.IL-10可抑制树突状细胞的成熟及产生IL-12,有助于树突状细胞诱导Th2反应.内源性或外源性IL-10在树突状细胞诱导无能/调节T细胞中具有重要作用。
马教授解释说，IL-10的产生必须保持一种非常精细的平衡才能有利于健康。IL-10水平太高会使身体更易受病毒和癌症等的攻击，并且容易导致自身免疫疾病的发生。但是，如果这种技术的量太少则会导致炎症病原物逃走。因此，对IL-10调节系统的了解会让我们进一步了解这些疾病并更好地治疗这些疾病。
每一秒，身体中数百万的细胞都在发生着天然的程序性细胞死亡，即细胞凋亡。在健康的个体中，这些将死或已死的细胞被做上记号，然后被免疫系统的清道夫细胞（例如巨噬细胞，生物谷注）快速消化和移除。但是，为了预防这种类型的清理引发更广泛的免疫应答，巨噬细胞会在凋亡细胞存在时会表达IL-10。IL-10能够抑制免疫系统T细胞的活性。
之前的研究已经证明巨噬细胞表面上一个叫做CD36的蛋白质受体对巨噬细胞识别凋亡细胞非常重要。在这项新的研究中，研究人员发现CD36还能够有助于触发凋亡细胞周围IL-10的制造。
研究然后由进一步提出了一个更深入的问题：到底是什么信号导致在CD36存在时制造IL-10？为了找出答案，这个研究组首先让巨噬细胞接触凋亡细胞。然后，他们利用灵敏的分析方法查看CD36活化下游发生的关键生化变化。
最终，他们发现了细胞核中与IL-10制造关键位点相结合的蛋白质。然后，研究组又顺藤摸瓜鉴定出了两个负责编码这些蛋白质转录本的基因。这两个分别叫做Pbx-1（pre-B transcription factor1）和Prep-1（Pbx-regulating protein1）的基因对研究人员来说相当熟悉。之前已经知道它们在胚胎发育和多种类型的白细胞中起到重要作用，并且Pbx在造血过程中起到关键作用。
马教授表示，他们目前还没有确定出Pbx-1和Prep-1到底是如何调节IL-10转录的。但是，他希望他们的这项研究能够为免疫学家发现全新的生化途径开辟一条新的道路。这项研究的发现也揭示出了有关异常的IL-10表达如何导致疾病的新信息。
白介素是由多种细胞产生并作用于多种细胞的一类细胞因子。由于最初是由白细胞产生又在白细胞间发挥作用，所以由此得名，现仍一直沿用。
1979年，研究人员在淋巴细胞活素及巨噬细胞因子（monoki－ne）中，发现并提纯了一种为白细胞间[杀菌]素的因子。最初测定的为 IL1和IL2。IL1属于monokine，以前曾以淋巴细胞活化因子（lymphocyte activating factor）。细胞促进蛋白质（mitogenic protein）以及B细胞活化因子（B cell－activating factor）等七种名称称之。而IL2属于淋巴细胞活素，以前曾以胸腺细胞刺激因子（thymocyte stimulating factor）、 T细胞生长因子（T cell growth factor）等六种名称称之。目前发现了29个白细胞介素，分别命名为IL-1---IL29.功能复杂，成网络，复杂重叠。
生物谷推荐原始出处：
Immunity, Vol 27, 952-964, 21 December 2007
Article
Interleukin-10 Expression in Macrophages during Phagocytosis of Apoptotic Cells Is Mediated by Homeodomain Proteins Pbx1 and Prep-1
Elaine Y. Chung,1,4,6 Jianguo Liu,1,6 Yoichiro Homma,1 Yunhua Zhang,1 Andrea Brendolan,2 Matilde Saggese,2 Jihong Han,3 Roy Silverstein,5 Licia Selleri,2 and Xiaojing Ma1,4,6,
1 Department of Microbiology and Immunology, Medical College of Cornell University, New York, NY 10065, USA
2 Department of Cell and Developmental Biology, Medical College of Cornell University, New York, NY 10065, USA
3 Department of Pathology and Laboratory Medicine Weill, Medical College of Cornell University, New York, NY 10065, USA
4 Graduate Program in Immunology and Microbial Pathogenesis, Weill Graduate School of Medical Sciences, Cornell University, 1300 York Avenue, New York, NY 10021, USA
5 Department of Cell Biology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA
Corresponding author
Xiaojing Ma
xim2002@med.cornell.edu
Summary
Production of interleukin (IL)-10, a major immunoregulatory cytokine, by phagocytes during clearance of apoptotic cells is critical to ensuring cellular homeostasis and suppression of autoimmunity. Little is known about the regulatory mechanisms in this fundamental process. We report that IL-10 production stimulated by apoptotic cells was regulated at the point of transcription in a manner dependent on p38 mitogen-activated protein kinase, partially on the scavenger receptor CD36, and required cell-cell contact but not phagocytosis. By using a reporter assay, we mapped the apoptotic-cell-response element (ACRE) in the human IL10 promoter and provide biochemical and physiological evidence that ACRE mediates the transcriptional activation of IL10 by pre-B cell leukemia transcription factor-1b and another Hox cofactor Pbx-regulating protein 1 in response to apoptotic cells. This study establishes a role of two developmentally critical factors (Pbx1 and Prep-1) in the regulation of homeostasis in the immune system.
小知识：
十多年来，美国宾夕法尼亚州大学医学院的Wafik S.El-Deiry教授一直都在研究一种癌症靶向分子TRAIL和它的分子搭档。TRAIL通常是由免疫细胞产生，能够通过与种类表面一种特化的受体结合来抑制种类的扩散。
在免疫力常常被抑制的癌症患者中，不能产生足够量的TRAIL，因此种类不能被抑制。
就在最近，El-Deiry和同事首次证实TRAIL受体和癌症敏感性之间的联系。这项研究的结果发表在12月13日的《临床检查杂志》（Journal of Clinical Investigation）网络版，2008年1月发表在印刷版上。出乎意料的是，他们还发现了炎症和癌症敏感性之间的一种由Trail介导的联系。
与对照小鼠相比，细胞上缺失TRAIL受体的小鼠，在进行化疗或放疗后，其肝脏和其他器官中形成更多、更大的肿瘤。研究组还繁育了TRAIL敲除小鼠。与对照相比，它们的后代发生了更多的肝脏肿瘤。这是证实肿瘤死亡诱导TRAIL受体的丧失导致癌症敏感性的首个直接的活体证据。
当完好无缺时，TRAIL和它的受体能够减少炎症细胞和导致癌症的分子。新的癌症模型暗示出炎症与癌症直接的一种联系。
现在，El-Deiry和他的研究组增在肿瘤组织中寻找炎症分子，从而希望能够了解癌症和炎症如何相互协作。
生物谷推荐英文原文：
J. Clin. Invest. 117:3658-3660 (2007). doi:10.1172/JCI34251.
Targeting mutant p53 shows promise for sunscreens and skin cancer
Wafik S. El-Deiry
Department of Medicine, Division of Hematology/Oncology, Department of Genetics, Department of Pharmacology, Abramson Comprehensive Cancer Center, and Institute for Translational Medicine and Therapeutics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
Address correspondence to: Wafik S. El-Deiry, Department of Medicine, University of Pennsylvania School of Medicine, 415 Curie Blvd., CRB 437, Philadelphia, Pennsylvania 19104, USA. Phone: (215) 898-9015; Fax: (215) 573-9139; E-mail: wafik@mail.med.upenn.edu .
Chronic exposure to UV light is a risk factor for skin cancer in which signature mutations in the p53 tumor suppressor gene occur due to DNA damage and contribute to cancer development. In this issue of the JCI, Tang et al. report on their study of a nonimmunodeficient mouse model of UVB-induced skin cancer and human skin carcinoma cells and show that the mutant p53 conformation–modifying drug CP-31398 not only treats these tumors but also prevents them (see the related article beginning on page 3753). These studies have important implications for chemoprevention as well as therapy of common, mutant p53–driven tumors.
According to the American Cancer Society (1), most of the more than 1 million cases of nonmelanoma skin cancer diagnosed yearly in the United States are considered to be sun related. Nonmelanoma skin cancer, which is the most common type of cancer affecting humans, occurs in either basal cells or squamous cells, and cancers typically occur in sun-exposed areas. Most skin cancers are caused by UV light exposure of the skin to sunlight or man-made tanning lamps (1). There is strong epidemiologic evidence supporting a relationship between UV light exposure and nonmelanoma skin cancer and growing evidence of a relationship between indoor tanning and melanoma (2).
Figure 1
Targeting mutant p53 to prevent or treat UV light–induced skin cancer. UV light exposure from bright sunlight or tanning beds leads to p53 mutations that contribute to skin cancer development in most of the 1 million individuals diagnosed with nonmelanoma skin cancer in the US each year. In a report in this issue of the JCI, Tang et al. (17) demonstrate that CP-31398 (13) can prevent UVB-induced tumor development as well as serve as an effective treatment for tumors that develop in an immunocompetent mouse model. CP-31398 appears to promote apoptosis by restoring wild-type p53 activity to mutated p53, leading to increased proapoptotic Bax expression, reduced antiapoptotic Bcl2 expression, and cytochrome c release from mitochondria. The inset shows the spectrum of p53 mutations observed in human squamous cell cancer of the skin that is associated with UVB exposure (UMD p53 mutation database: http://p53.free.fr/Database/p53_cancer/p53_skin.html). Mutations occur at particular hot spots with greater frequency, leading to loss of p53 tumor suppressor function. BCC, basal cell carcinoma.
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