Shin Jin Na, Park Sun-Young, Cha Jong Hee, Park Jae Yoon, Lee Byung Rai, Jung Sun-Ah, Lee Seung-Taek, Yun Cheol-Won, Seol Dai-Wu, Kim Tae-Hyoung
Department of Biochemistry, Chosun University School of Medicine, 375 Seosuk-Dong, Dong-Gu, Gwangju 501-759, Republic of Korea.
Exp Cell Res. 2006 Nov 15;312(19):3892-8. doi: 10.1016/j.yexcr.2006.08.015. Epub 2006 Aug 25.
TRAIL has been suggested to induce the cell death in various tumor cells but not in normal cells; however, several studies have provided the evidence that TRAIL can induce the cell death in some normal cells including human normal hepatocytes, suggesting that TRAIL may show hepatic toxicity in human. In this study, we designed a pro-form of TRAIL (sTRAIL:IL-18) in that soluble TRAIL (sTRAIL) is fused to IL-18, and a matrix metalloproteinases (MMPs) cleavage site is introduced at the connecting site. We showed that sTRAIL:IL-18 has significantly diminished the killing activity in HeLa cells but regains the activity by releasing the free sTRAIL through MMP-2-mediated cleavage. In addition, the killing activity of sTRAIL:IL-18 was significantly increased in HeLa cells when active MMP-2 was produced by TNF-alpha. Taken together, the data suggested that the sTRAIL:IL-18 can be reactivated at the specialized areas where MMPs are pathologically produced.
肿瘤坏死因子相关凋亡诱导配体（TRAIL）已被证明可诱导多种肿瘤细胞死亡，但对正常细胞无此作用；然而，多项研究已提供证据表明，TRAIL可诱导包括人正常肝细胞在内的一些正常细胞死亡，这表明TRAIL可能对人体具有肝毒性。在本研究中，我们设计了一种TRAIL的前体形式（sTRAIL:IL-18），其中可溶性TRAIL（sTRAIL）与IL-18融合，并在连接部位引入了基质金属蛋白酶（MMPs）切割位点。我们发现，sTRAIL:IL-18在HeLa细胞中的杀伤活性显著降低，但通过MMP-2介导的切割释放游离sTRAIL后可恢复活性。此外，当TNF-α产生活性MMP-2时，HeLa细胞中sTRAIL:IL-18的杀伤活性显著增加。综上所述，数据表明sTRAIL:IL-18可在MMPs病理产生的特定区域重新激活。
