The long pentraxin PTX3 up-regulates tissue factor in activated monocytes: another link between inflammation and clotting activation.
Pentraxin-3 (PTX3), an acute-phase protein that belongs to the family of the PTXs, is found elevated in septic shock and increased in patients with acute myocardial infarction. As tissue factor (TF) plays a key role in thrombosis and inflammation associated with atherosclerosis and as we have recently reported that PTX3 increases TF synthesis in endothelial cells, we tested whether PTX3 could modulate TF expression in monocytes. Monocytes from peripheral blood of healthy donors were incubated with highly purified PTX3 with or without lipopolysaccharide (LPS). Cells were then disrupted, and procoagulant activity was assessed by a one-stage clotting time. PTX3 enhanced TF activity and antigen from LPS-stimulated monocytes in a dose-dependent way. The effect was specific, as other PTXs, such as C-reactive protein and serum amyloid P component, were ineffective. Moreover, the increase in activity was specific for LPS, as in the presence of other TF-inducing agents such as interleukin-1beta and tumor necrosis factor alpha, PTX3 was not effective. The increase in TF activity requires mRNA synthesis, as assessed by polymerase chain reaction. The mechanism by which PTX3 modulates TF synthesis resides in an enhanced IkappaB, alpha phosphorylation and degradation and increased migration of the transacting factor c-Rel/p65 into the nucleus, as determined by Western blot and electro-mobility shift assay. These results show that PTX3 is an enhancer of the expression of TF by mononuclear cells. In the area of vascular injury, during the inflammatory response, cell-mediated fibrin deposition takes place. PTX3 increases TF expression, thus potentially playing a role in thrombogenesis and wound healing.
Napoleone
Emanuela
E
Istituto Ricerche Farmacologiche Mario Negri, Consorzio Mario Negri Sud, Via Nazionale, 66030 S. Maria Imbaro, Italy.
di Santo
Angelomaria
A
Peri
Giuseppe
G
Mantovani
Alberto
A
de Gaetano
Giovanni
G
Donati
Maria Benedetta
MB
Lorenzet
Roberto
R
D001777:Blood Coagulation / Q000502:physiology*; D015153:Blotting, Western; D002097:C-Reactive Protein / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D024202:Electrophoretic Mobility Shift Assay; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D007249:Inflammation / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D009000:Monocytes / Q000187:drug effects* / Q000378:metabolism; D010766:Phosphorylation; D016133:Polymerase Chain Reaction; D020569:Proto-Oncogene Proteins c-rel / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D000683:Serum Amyloid P-Component / Q000494:pharmacology*; D013925:Thromboplastin / Q000187:drug effects* / Q000378:metabolism; D015854:Up-Regulation; D000099153:Pentraxins
D002097:C-Reactive Protein; D020672:I-kappa B Proteins; D008070:Lipopolysaccharides; D020569:Proto-Oncogene Proteins c-rel; D012333:RNA, Messenger; D000683:Serum Amyloid P-Component; D013925:Thromboplastin; D000099153:Pentraxins