Influence of lipoxin A(4) and other lipoxygenase-derived eicosanoids on tissue factor expression.
Lipoxins (LX) are eicosanoids generated via transcellular biosynthetic routes during inflammation, hypersensitivity reaction, and after angioplasty. LXs are modulators of leukocyte trafficking and vascular tone. Their influence on the coagulation cascade has not been determined. In this study, we evaluated the influence of LXs on the expression of tissue factor (TF), a key regulator of coagulation. TF activity was measured in lysates of monocytes, human umbilical vein endothelial cells, and ECV304 cells using a one-stage clotting assay. LXA(4) stimulated TF activity in each cell type. The influence of LXA(4) on TF activity by ECV304 cells was studied further to explore the mechanism of induction of TF expression. LXA(4)-induced TF activity was dose dependent, cycloheximide sensitive, and associated with increased TF mRNA levels. Induction of TF activity was specific for LXA(4) and was not observed with LXB(4), the other major lipoxin generated by mammalian cells. Furthermore, ECV304 cell TF expression was not influenced by 15(R/S)-methyl-LXA(4) or 16-phenoxy-LXA(4), synthetic analogs of LXA(4) that activate the myeloid LXA(4) receptor, and was not modulated by SKF-104353, which blocks LXA(4) bioactivities transduced through the putative shared LXA(4)/LTD(4) receptor. LXA(4)-stimulated TF expression was blunted by pertussis toxin and by GF-109203X, an inhibitor of protein kinase C, and was not associated with degradation of IkappaBalpha. Our results establish that LXA(4) induces TF activity via cell signaling pathways with different structural and receptor requirements from those described for inhibition of leukocyte-endothelial cell interactions. They suggest a role for LXA(4) as a modulator of TF-related vascular events during inflammation and thrombosis.
Maderna
P
P
Centre for Molecular Inflammation and Vascular Research, Department of Medicine and Therapeutics, Mater Misericordiae Hospital, The Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin 7, Ireland.
Godson
C
C
Hannify
G
G
Murphy
M
M
Brady
H R
HR
D016718:Arachidonic Acid / Q000378:metabolism / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015777:Eicosanoids / Q000378:metabolism* / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000378:metabolism; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000378:metabolism / Q000494:pharmacology; D020672:I-kappa B Proteins; D044045:Lipoxins; D008084:Lipoxygenase / Q000378:metabolism*; D009000:Monocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha; D037342:Pertussis Toxin; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors / Q000378:metabolism; D044042:Receptors, Formyl Peptide; D044067:Receptors, Lipoxin; D015398:Signal Transduction / Q000187:drug effects; D013329:Structure-Activity Relationship; D013925:Thromboplastin / Q000096:biosynthesis* / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
D004268:DNA-Binding Proteins; D015777:Eicosanoids; D004791:Enzyme Inhibitors; C105101:FPR2 protein, human; D006893:Hydroxyeicosatetraenoic Acids; D020672:I-kappa B Proteins; D044045:Lipoxins; C000606204:NFKBIA protein, human; D011500:Protein Synthesis Inhibitors; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D044042:Receptors, Formyl Peptide; D044067:Receptors, Lipoxin; D014409:Tumor Necrosis Factor-alpha; D010566:Virulence Factors, Bordetella; C040527:lipoxin A4; D000072000:NF-KappaB Inhibitor alpha; D016718:Arachidonic Acid; D013925:Thromboplastin; D008084:Lipoxygenase; D037342:Pertussis Toxin; D019206:GTP-Binding Protein alpha Subunits, Gi-Go