Induction of tissue factor expression in human monocytic cells by protease inhibitors through activating activator protein-1 (AP-1) with phosphorylation of Jun-N-terminal kinase and p38.
Tissue factor (TF) is expressed rapidly by human monocytes exposed to a variety of agonists such as lipopolysaccharide (LPS) or tumor necrosis factor-alpha. Activation of both activator protein-1 (AP-1; c-Jun/c-Fos) and nuclear factor-kappaB (NF-kappaB) pathways is necessary for maximal induction of the TF gene. It has been demonstrated that activation of both AP-1 and NF-kappaB is correlated with the degradation of both phosphorylated c-Jun and inhibitor kappaB (IkappaB) by proteasome. The present study was designed to investigate whether various protease inhibitors, including proteasome inhibitors, affect TF expression in monocytic cells. Protease inhibitors, 3,4-dichloroisocoumarin (DCI), N-tosyl-l-phenylalanine chloromethyl ketone (TPCK), and N-acetyl-Leu-Leu-norleucinal (ALLN) induced TF activity in monocytic cells in a dose- and time-dependent manner at the level of the transcription of the TF gene, which was mediated through inducing phosphorylation of both Jun-N-terminal kinase and p38. The early growth response-1 (Egr-1) pathway was not affected. The NF-kappaB pathway was not activated; rather it was inhibited. These results were distinct from the findings previously reported for LPS-stimulated cells. The present study demonstrated that some protease inhibitors might act as stress and induced TF expression with direct phosphorylation of JNK and p38, followed by phosphorylation and activation of AP-1 in monocytic cells. This evidence may help elucidate further regulatory mechanisms of TF induction, and might have physiological significance for the clinically challenged use of proteasome inhibitors. In addition to phosphorylation of JNK and p38, an unknown signal pathway needs to be clarified for TF induction.
Ohsawa
Mai
M
Laboratory Medicine, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan.
Koyama
Takatoshi
T
Nara
Nobuo
N
Hirosawa
Shinsaku
S
D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D007700:Kinetics; D009000:Monocytes / Q000378:metabolism*; D010766:Phosphorylation; D011480:Protease Inhibitors / Q000494:pharmacology*; D013925:Thromboplastin / Q000187:drug effects / Q000235:genetics*; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D011480:Protease Inhibitors; D018808:Transcription Factor AP-1; D013925:Thromboplastin; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases