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Possible role of Marcks in the cellular modulation of monocytic tissue factor‐initiated hypercoagulation
Author(s) -
Chu Arthur J.,
Lin ShiHua,
Piasentin Evano
Publication year - 2002
Publication title -
british journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.907
H-Index - 186
eISSN - 1365-2141
pISSN - 0007-1048
DOI - 10.1046/j.1365-2141.2002.03611.x
Subject(s) - marcks , downregulation and upregulation , tissue factor , lipopolysaccharide , chemistry , biology , phosphorylation , microbiology and biotechnology , protein kinase c , coagulation , medicine , immunology , biochemistry , gene
Summary. The enhanced extrinsic tissue factor (TF)‐initiated coagulation, often resulting from sepsis, could lead to disseminated intravascular coagulation presenting cardiovascular complications. Using model human leukaemia THP‐1 monocytes, we studied monocytic TF (mTF) hypercoagulation and its regulation. After an 8 h exposure to bacterial endotoxin [lipopolysaccharide (LPS); 100 ng/ml], mTF activity was significantly upregulated as the result of the enhanced mTF synthesis. Thereafter, LPS induction declined, exhibiting a ‘quiescent‐desensitizing’ phenomenon. Such diminished LPS induction was,however,associated with sustained LPS‐enhanced mTF synthesis, revealing the possible occurrence of a post‐translationaldownregulation. It was noted that LPS desensitization was accompanied by the increased expression of myristoylated alanine‐rich C kinase substrate (Marcks). In contrast, A23187 (20 µmol/l) or Quin‐2AM (20 µmol/l) drastically activated mTF activity without detectable effect on mTF synthesis; both of which showed that sustained functional upregulation during 24 h culture did not enhance Marcks expression. These inverse correlations between mTF activity upregulation and Marcks expression suggested that Marcks could be inhibitory. Marcks phosphorylation site domain (151–175) (Marcks PSD) readily inhibited mTF‐dependent FVII activation and diminished FVIIa formation in LPS‐challenged cells. As a result, Marcks PSD offset LPS‐induced mTF hypercoagulation upon inclusion in the single‐stage clotting assays. The anticoagulant activity was confirmed by showing that Marcks PSD significantly blocked rabbit brain thromboplastin (rbTF) procoagulation and inhibited rbTF‐dependent FVII activation as well as FVIIa formation. Our study suggests that Marcks expression plays a role in a novel cellular modulation to downregulate mTF hypercoagulation.