Titanium dioxide nanoparticles induce apoptosis through the JNK/p38-caspase-8-Bid pathway in phytohemagglutinin-stimulated human lymphocytes.
We investigated the signaling pathways underlying nano-TiO(2)-induced apoptosis in cultured human lymphocytes. Nano-TiO(2) increased the proportion of sub-G1 cells, activated caspase-9 and caspase-3, and induced caspase-3-mediated PARP cleavage. Nano-TiO(2) also induced loss of mitochondrial membrane potential, which suggests that nano-TiO(2) induces apoptosis via a mitochondrial pathway. A time-sequence analysis of the induction of apoptosis by nano-TiO(2) revealed that nano-TiO(2) triggered apoptosis through caspase-8/Bid activation. We also observed that inhibition of caspase-8 by z-IETD-fmk suppressed the caspase-8/Bid activation, caspase-3-mediated PARP cleavage, and apoptosis. Nano-TiO(2) activated two MAPKs, p38 and JNK. In addition, the selective p38 inhibitor SB203580 and selective JNK inhibitor SP600125 suppressed nano-TiO(2)-induced apoptosis and caspase-8 activation to moderate and significant extents, respectively. Knockdown of protein levels of JNK1 and p38 using an RNA interference technique also suppressed caspase-8 activation. Our results suggest that nano-TiO(2)-induced apoptosis is mediated by the p38/JNK pathway and the caspase-8-dependent Bid pathway in human lymphocytes.
Kang
Su Jin
SJ
School of Public Health and Institute of Health and Environment, Seoul National University, 28 Yunkeun-dong, Chongno-ku, Seoul 110-460, Republic of Korea.
Kim
Byeong Mo
BM
Lee
Young Joon
YJ
Hong
Sung Hee
SH
Chung
Hai Won
HW
D017209:Apoptosis; D051023:BH3 Interacting Domain Death Agonist Protein / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D061945:Caspase Inhibitors; D002478:Cells, Cultured; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D006801:Humans; D008213:Lymphocyte Activation / Q000187:drug effects*; D008214:Lymphocytes / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D048670:MAP Kinase Kinase 4 / Q000037:antagonists & inhibitors / Q000378:metabolism; D053758:Nanoparticles; D009842:Oligopeptides / Q000494:pharmacology; D010835:Phytohemagglutinins / Q000494:pharmacology; D014025:Titanium / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D051023:BH3 Interacting Domain Death Agonist Protein; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D009842:Oligopeptides; D010835:Phytohemagglutinins; C403753:benzyloxycarbonyl-isoleucyl-glutamyl-threonyl-aspartic acid fluoromethyl ketone; C009495:titanium dioxide; D014025:Titanium; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D053181:Caspase 8