生物谷報道：美國Weill康奈爾醫(yī)學(xué)院的一個研究組鑒定出兩個基因?qū)Ξa(chǎn)生一種免疫系統(tǒng)細(xì)胞激素IL-10（白介素－10）至關(guān)重要,。研究的結(jié)果發(fā)表在12月的Immunity雜志上。這項研究的首席研究人員是華人科學(xué)家馬小京教授,。參與這項研究的還有Weill康奈爾的劉建國（Jianguo Liu，音譯）博士,、Elain Y. Chung,。
這一發(fā)現(xiàn)填補了與從紅斑狼瘡和I型糖尿病到癌癥和艾滋病的一系列疾病相關(guān)的一個生物化學(xué)途徑的一個重要的“迷失鏈條”。
IL-10是一種重要的抗炎性細(xì)胞因子,近年發(fā)現(xiàn)在樹突狀細(xì)胞的免疫調(diào)控中具有重要作用.IL-10可抑制樹突狀細(xì)胞的成熟及產(chǎn)生IL-12,有助于樹突狀細(xì)胞誘導(dǎo)Th2反應(yīng).內(nèi)源性或外源性IL-10在樹突狀細(xì)胞誘導(dǎo)無能/調(diào)節(jié)T細(xì)胞中具有重要作用,。
馬教授解釋說,，IL-10的產(chǎn)生必須保持一種非常精細(xì)的平衡才能有利于健康。IL-10水平太高會使身體更易受病毒和癌癥等的攻擊,，并且容易導(dǎo)致自身免疫疾病的發(fā)生,。但是,，如果這種技術(shù)的量太少則會導(dǎo)致炎癥病原物逃走。因此,，對IL-10調(diào)節(jié)系統(tǒng)的了解會讓我們進(jìn)一步了解這些疾病并更好地治療這些疾病,。
每一秒，身體中數(shù)百萬的細(xì)胞都在發(fā)生著天然的程序性細(xì)胞死亡,，即細(xì)胞凋亡,。在健康的個體中，這些將死或已死的細(xì)胞被做上記號,，然后被免疫系統(tǒng)的清道夫細(xì)胞（例如巨噬細(xì)胞,，生物谷注）快速消化和移除。但是,，為了預(yù)防這種類型的清理引發(fā)更廣泛的免疫應(yīng)答,，巨噬細(xì)胞會在凋亡細(xì)胞存在時會表達(dá)IL-10。IL-10能夠抑制免疫系統(tǒng)T細(xì)胞的活性,。
之前的研究已經(jīng)證明巨噬細(xì)胞表面上一個叫做CD36的蛋白質(zhì)受體對巨噬細(xì)胞識別凋亡細(xì)胞非常重要,。在這項新的研究中，研究人員發(fā)現(xiàn)CD36還能夠有助于觸發(fā)凋亡細(xì)胞周圍IL-10的制造,。
研究然后由進(jìn)一步提出了一個更深入的問題：到底是什么信號導(dǎo)致在CD36存在時制造IL-10,？為了找出答案，這個研究組首先讓巨噬細(xì)胞接觸凋亡細(xì)胞,。然后,，他們利用靈敏的分析方法查看CD36活化下游發(fā)生的關(guān)鍵生化變化。
最終,，他們發(fā)現(xiàn)了細(xì)胞核中與IL-10制造關(guān)鍵位點相結(jié)合的蛋白質(zhì),。然后，研究組又順藤摸瓜鑒定出了兩個負(fù)責(zé)編碼這些蛋白質(zhì)轉(zhuǎn)錄本的基因,。這兩個分別叫做Pbx-1（pre-B transcription factor1）和Prep-1（Pbx-regulating protein1）的基因?qū)ρ芯咳藛T來說相當(dāng)熟悉,。之前已經(jīng)知道它們在胚胎發(fā)育和多種類型的白細(xì)胞中起到重要作用，并且Pbx在造血過程中起到關(guān)鍵作用,。
馬教授表示,，他們目前還沒有確定出Pbx-1和Prep-1到底是如何調(diào)節(jié)IL-10轉(zhuǎn)錄的。但是,，他希望他們的這項研究能夠為免疫學(xué)家發(fā)現(xiàn)全新的生化途徑開辟一條新的道路,。這項研究的發(fā)現(xiàn)也揭示出了有關(guān)異常的IL-10表達(dá)如何導(dǎo)致疾病的新信息。
白介素是由多種細(xì)胞產(chǎn)生并作用于多種細(xì)胞的一類細(xì)胞因子,。由于最初是由白細(xì)胞產(chǎn)生又在白細(xì)胞間發(fā)揮作用,，所以由此得名，現(xiàn)仍一直沿用,。
1979年,，研究人員在淋巴細(xì)胞活素及巨噬細(xì)胞因子（monoki－ne）中,，發(fā)現(xiàn)并提純了一種為白細(xì)胞間[殺菌]素的因子。最初測定的為 IL1和IL2,。IL1屬于monokine,，以前曾以淋巴細(xì)胞活化因子（lymphocyte activating factor）。細(xì)胞促進(jìn)蛋白質(zhì)（mitogenic protein）以及B細(xì)胞活化因子（B cell－activating factor）等七種名稱稱之,。而IL2屬于淋巴細(xì)胞活素,，以前曾以胸腺細(xì)胞刺激因子（thymocyte stimulating factor）、 T細(xì)胞生長因子（T cell growth factor）等六種名稱稱之,。目前發(fā)現(xiàn)了29個白細(xì)胞介素,，分別命名為IL-1---IL29.功能復(fù)雜，成網(wǎng)絡(luò),，復(fù)雜重疊,。
生物谷推薦原始出處：
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
[email protected]
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.
小知識：
十多年來，美國賓夕法尼亞州大學(xué)醫(yī)學(xué)院的Wafik S.El-Deiry教授一直都在研究一種癌癥靶向分子TRAIL和它的分子搭檔,。TRAIL通常是由免疫細(xì)胞產(chǎn)生,，能夠通過與種類表面一種特化的受體結(jié)合來抑制種類的擴(kuò)散。
在免疫力常常被抑制的癌癥患者中,，不能產(chǎn)生足夠量的TRAIL,，因此種類不能被抑制。
就在最近,，El-Deiry和同事首次證實TRAIL受體和癌癥敏感性之間的聯(lián)系。這項研究的結(jié)果發(fā)表在12月13日的《臨床檢查雜志》（Journal of Clinical Investigation）網(wǎng)絡(luò)版,，2008年1月發(fā)表在印刷版上,。出乎意料的是，他們還發(fā)現(xiàn)了炎癥和癌癥敏感性之間的一種由Trail介導(dǎo)的聯(lián)系,。
與對照小鼠相比,，細(xì)胞上缺失TRAIL受體的小鼠，在進(jìn)行化療或放療后,，其肝臟和其他器官中形成更多,、更大的腫瘤。研究組還繁育了TRAIL敲除小鼠,。與對照相比,，它們的后代發(fā)生了更多的肝臟腫瘤。這是證實腫瘤死亡誘導(dǎo)TRAIL受體的喪失導(dǎo)致癌癥敏感性的首個直接的活體證據(jù),。
當(dāng)完好無缺時,，TRAIL和它的受體能夠減少炎癥細(xì)胞和導(dǎo)致癌癥的分子。新的癌癥模型暗示出炎癥與癌癥直接的一種聯(lián)系,。
現(xiàn)在,，El-Deiry和他的研究組增在腫瘤組織中尋找炎癥分子,，從而希望能夠了解癌癥和炎癥如何相互協(xié)作。
生物谷推薦英文原文：
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: [email protected] .
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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