近日,，來自美國羅格斯大學(xué)的研究者開發(fā)了一種新的激活機(jī)體免疫細(xì)胞阿片樣受體（opiate receptors）活性的新方法,，這樣免疫細(xì)胞就可以高效地對(duì)腫瘤細(xì)胞進(jìn)行清除。在研究中,，研究者Dipak Sarkar教授和其團(tuán)隊(duì)使用了一種新的藥理學(xué)途徑來激活免疫細(xì)胞,，最終達(dá)到抑制腫瘤細(xì)胞生長并且高效清除腫瘤細(xì)胞的目的。相關(guān)研究成果刊登在了5月11日的國際雜志Journal of Biological Chemistry上,。
研究者在文章中描述了兩種結(jié)構(gòu)不同但功能相似的阿片樣受體Mu和Delta受體,，免疫細(xì)胞中的這些來自蛋白復(fù)合物的受體要么是由兩個(gè)相同分子形成的結(jié)構(gòu)相似的同性二聚體受體，要么是由乙醇誘導(dǎo)形成的在結(jié)構(gòu)上不同的異源二聚體,。研究者用藥理學(xué)的方法使得這兩種結(jié)構(gòu)不同但功能相似的阿片樣受體Mu和Delta受體形成更多的同型二聚體,，以便這些受體可以在免疫細(xì)胞中激增，最終有能力殺死腫瘤細(xì)胞,。
研究者Sarkar表示,，這項(xiàng)研究的潛力就在于可以引起大腦中內(nèi)源性阿片類物質(zhì)的產(chǎn)生并且增加，而此時(shí),，大腦外圍的物質(zhì)將會(huì)變得更加有效,，來調(diào)節(jié)壓力以及免疫功能。阿片樣物質(zhì)就像大腦內(nèi)啡肽類,，可以和免疫細(xì)胞進(jìn)行交流溝通,，因此當(dāng)胎兒因?yàn)榻佑|酒精、藥物濫用,、焦慮,、壓抑、慢性心理壓力等原因而引起大腦內(nèi)啡肽缺失的話,，胎兒的機(jī)體就會(huì)經(jīng)歷壓力沖擊,，最終引起免疫機(jī)能不全。阿片樣物質(zhì)就扮演著調(diào)節(jié)機(jī)體壓力機(jī)制的調(diào)節(jié)子的作用，因此當(dāng)機(jī)體中內(nèi)啡肽類水平較低的話,，機(jī)體的壓力指示器水平就會(huì)升高,。
研究者的這項(xiàng)研究中，研究者將Mu受體阻滯劑和Delta受體的激活劑進(jìn)行結(jié)合后,，免疫細(xì)胞就會(huì)增加外源細(xì)胞殺傷的能力,，這將會(huì)使得機(jī)體更加有效地抵御病原菌感染和腫瘤細(xì)胞的生長。Sarkar認(rèn)為,，將阿片類拮抗劑和激活劑進(jìn)行結(jié)合對(duì)于人類疾病有潛在的治療價(jià)值,，尤其是對(duì)于免疫不全者、癌癥患者,、病痛患者以及酒精依賴性疾病的患者,。以前研究室的研究表明，在細(xì)胞治療中補(bǔ)充內(nèi)啡肽類可以阻止很多壓力以及免疫問題,，然而,，細(xì)胞治療比較復(fù)雜，涉及神經(jīng)干細(xì)胞產(chǎn)生內(nèi)啡肽類細(xì)胞的復(fù)雜過程,，并且有時(shí)候會(huì)導(dǎo)致產(chǎn)生其它病癥,。
研究者開展這項(xiàng)研究的興趣基于他們通過觀察發(fā)現(xiàn)，酒精濫用或有其它發(fā)育問題的母親經(jīng)常會(huì)生育出有高壓效應(yīng),、癌癥或者免疫系統(tǒng)疾病的孩子,，研究者為了追尋這種孩子的發(fā)病機(jī)制，所以開展了這項(xiàng)研究,，研究者通過部分調(diào)查研究表示,，內(nèi)源性的阿片樣系統(tǒng)在高壓效應(yīng)孩子和承認(rèn)的大腦中是異常的。
研究組還發(fā)現(xiàn)了當(dāng)人們酗酒時(shí),，機(jī)體抵御病毒,、細(xì)菌或者癌癥發(fā)生的能力會(huì)下降?？偟膩碚f,，研究者的這項(xiàng)研究增加了我們對(duì)于新式的治療癌癥、免疫系統(tǒng)疾病以及酒精誘導(dǎo)疾病的方法的理解,。研究者還希望這種新式的藥理學(xué)方法可以激起免疫細(xì)胞的阿片樣受體的活性,，使得離臨床治療更近一步。
（生物谷：T.Shen編譯）
doi:10.1074/jbc.M112.347583
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Opiate Antagonist Prevents μ- and δ-Opiate Receptor Dimerization to Facilitate Ability of Agonist to Control Ethanol-altered Natural Killer Cell Functions and Mammary Tumor Growth*
Dipak K. Sarkar1, Amitabha Sengupta, Changqing Zhang, Nadka Boyadjieva and Sengottuvelan Murugan
In the natural killer (NK) cells, δ-opiate receptor (DOR) and μ-opioid receptor (MOR) interact in a feedback manner to regulate cytolytic function with an unknown mechanism. Using RNK16 cells, a rat NK cell line, we show that MOR and DOR monomer and dimer proteins existed in these cells and that chronic treatment with a receptor antagonist reduced protein levels of the targeted receptor but increased levels of opposing receptor monomer and homodimer. The opposing receptor-enhancing effects of MOR and DOR antagonists were abolished following receptor gene knockdown by siRNA. Ethanol treatment increased MOR and DOR heterodimers while it decreased the cellular levels of MOR and DOR monomers and homodimers. The opioid receptor homodimerization was associated with an increased receptor binding, and heterodimerization was associated with a decreased receptor binding and the production of cytotoxic factors. Similarly, in vivo, opioid receptor dimerization, ligand binding of receptors, and cell function in immune cells were promoted by chronic treatment with an opiate antagonist but suppressed by chronic ethanol feeding. Additionally, a combined treatment of an MOR antagonist and a DOR agonist was able to reverse the immune suppressive effect of ethanol and reduce the growth and progression of mammary tumors in rats. These data identify a role of receptor dimerization in the mechanism of DOR and MOR feedback interaction in NK cells, and they further elucidate the potential for the use of a combined opioid antagonist and agonist therapy for the treatment of immune incompetence and cancer and alcohol-related diseases.
