近日來自浙江大學生命科學學院細胞與發育生物學研究所的研究人員從硬骨魚中首次鑒別出Toll-IL-1受體家族的一個新成員DIGIRR，并證實其在IL-1信號通路中發揮重要的負調控作用。這一研究成果于7月29日在線發表在著名的免疫學期刊《免疫學期刊》（The Journal of Immunology）上。
Toll蛋白樣受體（TLR）是在研究果蠅胚胎腹背側體軸形成過程中新發現的一種介導機體天然免疫(innate immunity)的受體蛋白。因其結構、功能及信號轉導途徑均與白介素-1受體（IL-1R）類似，故統歸于Toll/IL-1R家族。哺乳動物Toll受體稱為Toll樣受體（Toll like receptors, TLRs）。迄今為止，10種人類TLRs(human TLRs,hTLRs)已被先后發現。近年來大量研究證實Toll/IL-1R家族成員在炎癥、免疫、病源體識別中都起著十分重要的作用，參與許多疾病的發病過程，與傳染病、腫瘤、心血管病、自身免 疫性疾病、過敏等都有著密切關系。它亦是研究和開發新藥的一個新的靶點，故受到國際醫學生物學廣泛關注。然而目前對科學家們其信號通路的負調控機制尚缺乏深入理解。
在這篇文章中，研究人員從三種硬骨魚模型中首次鑒定出該家族的一個新成員，命名為Double-Ig-IL-1R Related Molecule (DIGIRR)，并證實這個DIGIRR分子包含有兩個胞外Ig結構域，一個胞內Arg-Tyr536位點突TIR結構域，且定位于高爾基體的胞內受體。這些特征表明DIGIRR有別于其他已知的Toll/IL-1R家族成員。隨后研究人員在體外實驗中證實將DIGIRR注入到斑馬魚胚胎中可顯著抑制脂多糖（LPS）和IL-1β誘導的NF-κB激活。當研究人員在斑馬魚體內用小干擾RNA(siRNA)沉默DIGIRR基因表達時發現在DIGIRR沉默的肝腎組織及白細胞中IL-1β即促炎細胞因子IL-6的表達水平顯著增高。研究結果表明DIGIRR是LPS和IL-1β介導的信號傳導通路及炎癥反應中發揮重要的負調控因子作用。此外研究人員還證實一個胞外Ig結構域的缺失和胞內TIR結構域中Arg-Tyr536位點的突變，是IL-1R家族成員演化為負調節受體的重要機制。
浙江大學生命科學學院的邵建忠教授及項黎新副教授為這篇文章的共同通訊作者。這一研究獲得了國家基礎研究發展規劃（973）項目（2006CB101805）、國家高技術研究發展計劃（863）項目（2008AA09Z409）、國家自然科學基金（30871936, 31072234）以及浙江省科學技術基金（2007C12011）的資助。
Discovery of the DIGIRR Gene from Teleost Fish: A Novel Toll–IL-1 Receptor Family Member Serving as a Negative Regulator of IL-1 Signaling
Yi-feng Gu, Yu Fang, Yang Jin, Wei-ren Dong, Li-xin Xiang and Jian-zhong Shao
Toll–IL-1R (TIR) family members play crucial roles in a variety of defense, inflammatory, injury, and stress responses. Although they have been widely investigated in mammals, little is known about TIRs in ancient vertebrates. In this study, we report a novel double Ig IL-1R related molecule (DIGIRR) from three model fish (Tetraodon nigroviridis, Gasterosteus aculeatus, and Takifugu rubripes), adding a previously unknown homolog to the TIR family. This DIGIRR molecule contains two Ig-like domains in the extracellular region, one Arg-Tyr–mutated TIR domain in the intracellular region, and a unique subcellular distribution within the Golgi apparatus. These characteristics distinguish DIGIRR from other known family members. In vitro injection of DIGIRR into zebrafish embryos dramatically inhibited LPS-induced and IL-1β–induced NF-κB activation. Moreover, in vivo knockdown of DIGIRR by small interfering RNA significantly promoted the expression of IL-1β–stimulated proinflammatory cytokines (IL-6 and IL-1β) in DIGIRR-silenced liver and kidney tissues and in leukocytes. These results strongly suggest that DIGIRR is an important negative regulator of LPS-mediated and IL-1β–mediated signaling pathways and inflammatory responses. The Arg-Tyr–mutated site disrupted the signal transduction ability of DIGIRR TIR. Evolutionally, we propose a hypothesis that DIGIRR and single Ig IL-1R related molecule (SIGIRR) might originate from a common ancient IL-1R–like molecule that lost one (in DIGIRR) or two (in SIGIRR) extracellular Ig-like domains and intracellular Ser and Arg-Tyr amino acids. DIGIRR might be an evolutionary “transitional molecule” between IL-1R and SIGIRR, representing a shift from a potent receptor to a negative regulator. These results help define the evolutionary history of TIR family members and their associated signaling pathways and mechanisms.
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