Generation of a novel proform of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) protein that can be reactivated by matrix metalloproteinases.
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.
Shin
Jin Na
JN
Department of Biochemistry, Chosun University School of Medicine, 375 Seosuk-Dong, Dong-Gu, Gwangju 501-759, Republic of Korea.
Park
Sun-Young
SY
Cha
Jong Hee
JH
Park
Jae Yoon
JY
Lee
Byung Rai
BR
Jung
Sun-Ah
SA
Lee
Seung-Taek
ST
Yun
Cheol-Won
CW
Seol
Dai-Wu
DW
Kim
Tae-Hyoung
TH
D017209:Apoptosis; D001483:Base Sequence; D018076:DNA, Complementary / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D020382:Interleukin-18 / Q000235:genetics / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D011498:Protein Precursors / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D018076:DNA, Complementary; D020382:Interleukin-18; D011498:Protein Precursors; D011993:Recombinant Fusion Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; D020782:Matrix Metalloproteinases; D020778:Matrix Metalloproteinase 2