Tissue factor in neutrophils: yes
2004; Elsevier BV; Volume: 2; Issue: 2 Linguagem: Inglês
10.1111/j.1538-7836.2004.00548.x
ISSN1538-7933
AutoresS. Nakamura, Takahisa Imamura, Kohji Okamoto,
Tópico(s)Hemophilia Treatment and Research
ResumoTissue factor (TF, CD142 [Morrissey et al, 1997Morrissey J.M. Agis H. Albrecht S. Dignat‐George F. Edgington T.S. Luther T. Muller M. Mutin M. Nakamura S. Valent P. Vercellotti G.M. CD142 (tissue factor).in: Kishimoto K Kikutani H Borne A Goyert S Mason D Miyasaka M Leukocyte Typing IV. White Cell Differentiation Antigens. Garland Publishing, 1997: 742-6Google Scholar]) initiates blood clotting through interaction with factor (F)VII/VIIa. TF is also known to participate in signal transduction, angiogenesis, embryogenesis, or tumor metastasis [Rottingen et al, 1995Rottingen J.A. Enden T. Camerer E. Iversen J.G. Prydz H. Binding of human factor VIIa to tissue factor induces cytosolic Ca2+ signals in J82 cells, transfected COS‐1 cells, Madin‐Drby canine kidney cells and in human endothelial cells induced to synthesize tissue factor.J Biol Chem. 1995; 270: 4650-60Abstract Full Text Full Text PDF PubMed Scopus (183) Google Scholar, Masuda et al, 1996Masuda M. Nakamura S. Murakami T. Komiyama Y. Takahashi H. Association of tissue factor with a gamma chain homodimer of the IgE receptor type 1 in cultured human monocytes.Eur J Immunol. 1996; 26: 2529-32Crossref PubMed Scopus (40) Google Scholar, Zhang et al, 1994Zhang Y. Deng Y. Luther T. Muller M. Ziegle R. Waldherr R. Stern D.M. Nawroth P.P. Tissue factor controls the balance of angiogenic and antiangiogenic properties of tumor cells in mice.J Clin Invest. 1994; 94: 1320-7Crossref PubMed Scopus (465) Google Scholar, Carmeliet et al, 1996Carmeliet P. Mackman N. Moons L. Luther T. Gressens P. Vanvlaenderen I. Demunck H. Kasper M. Breier G. Evrard P. Muller M. Risau W. Edgington T. Collen D. Role of tissue factor in embryonic blood vessel development.Nature. 1996; 383: 73-5Crossref PubMed Scopus (588) Google Scholar, Bromberg et al, 1995Bromberg M.E. Konigsberg W.H. Madison J.F. Pawashe A. Garen A. Tissue factor promotes melanoma metastasis by a pathway independent of blood coagulation.Proc Natl Acad Sci USA. 1995; 92: 8205-9Crossref PubMed Scopus (285) Google Scholar]. Among the leukocytes, only monocytes have been reported to express TF, but others, neutrophils (polymorphonuclear leukocytes) or lymphocytes, have not. Neutrophilic leukocytes have been proposed to produce TF [Lerner et al, 1977Lerner R.G. Goldstein R. Nelson J.C. Production of thromboplastin (tissue factor) and thrombi by polymorphonuclear neutrophilic leukocytes adhering to vein walls.Thromb Res. 1977; 11: 11-22Abstract Full Text PDF PubMed Scopus (18) Google Scholar, Lerner et al, 1977Lerner R.G. Goldstein R. Cummings G. Endotoxin induced disseminated intravascular clotting: evidence that it is mediated by neutrophil production of tissue factor.Thromb Res. 1977; 11: 253-61Abstract Full Text PDF PubMed Scopus (26) Google Scholar], though there was little direct evidence to elucidate TF expression/production in these leukocytes. Recently we found TF expression in neutrophils accumulated at the liver sinusoid in lipopolysaccharide (LPS)‐mediated disseminated intravascular coagulation (DIC) in rabbit and monkey by immunohistochemical analysis [Higure et al, 1996Higure A. Okamoto K. Hirata K. Todoroki H. Nagafuchi Y. Takeda S. Katoh H. Itoh H. Ohsato K. Nakamura S. Macrophages and neutrophils infiltrating into the liver are responsible for tissue factor expression in a rabbit model of acute obstructive cholangitis.Thromb Haemost. 1996; 75: 791-5Crossref PubMed Scopus (50) Google Scholar, Todoroki et al, 1998Todoroki H. Higure A. Okamoto K. Okazaki K. Nagafuchi Y. Takeda S. Katoh H. Itoh H. Ohsato K. Nakamura S. Possible role of platelet‐activating factor in the in vivoexpression of tissue factor in neutrophils.J Surg Res. 1998; 80: 149-55Abstract Full Text PDF PubMed Scopus (22) Google Scholar, Todoroki et al, 2000Todoroki H. Nakamura S. Higure A. Okamoto K. Takeda S. Nagata N. Itoh H. Ohsato K. Neutrophils express tissue factor in a monkey model of sepsis.Surgery. 2000; 127: 209-16Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar]. We also observed neutrophil TF expression in infiltrated neutrophils at skin sites with Arthus reactions [Imamura et al, 2002Imamura T. Kaneda H. Nakamura S. New functions of neutrophils in the arthus reaction: expression of tissue factor, the clotting initiator, and fibrinolysis by elastase.Lab Invest. 2002; 82: 1287-95Crossref PubMed Scopus (19) Google Scholar]—here a type III allergy, and induced in monkeys using bovine serum albumin as antigen. TF expression in human neutrophils was also found in infiltrated and/or accumulated cells in peritonitis, appendicitis or brain‐damaged patients (unpublished data). These indicate a new function of neutrophils; that is, they express/produce TF in vivo, as do monocytes. Giesen et al. reported TF‐bearing neutrophils in an ex vivostudy using pig arterial media and collagen‐coated glass slides exposed to flowing native human blood [Giesen et al, 1999Giesen P.L. Rauch U. Bohrmann B. Kling D. Roque M. Fallon J.T. Badimon J.J. Himber J. Riederer M.A. Nemerson Y. Blood‐borne tissue factor: another view of thrombosis.Proc Natl Acad Sci USA. 1999; 96: 2311-5Crossref PubMed Scopus (921) Google Scholar]; but de novoTF production was not clear in their study. It was claimed that neutrophil TF was not an endogenous product but a foreign one produced in monocytes or endothelial cells. We detected TF mRNA in in vivoexaminations in neutrophils accumulated at inflammatory sites by in situhybridization using TF mRNA probes [Todoroki et al, 2000Todoroki H. Nakamura S. Higure A. Okamoto K. Takeda S. Nagata N. Itoh H. Ohsato K. Neutrophils express tissue factor in a monkey model of sepsis.Surgery. 2000; 127: 209-16Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar, Imamura et al, 2002Imamura T. Kaneda H. Nakamura S. New functions of neutrophils in the arthus reaction: expression of tissue factor, the clotting initiator, and fibrinolysis by elastase.Lab Invest. 2002; 82: 1287-95Crossref PubMed Scopus (19) Google Scholar]. This is direct evidence of de novosynthesis of TF in neutrophils through transcriptional events and indicates endogenous origin. Some reports have proposed a foreign source for neutrophil TF that was bound onto or internalized into neutrophils from platelets; TF‐bearing microvesicles were observed in the membrane of α‐granules and on the cell surface of platelets [Muller et al, 2003Muller I. Klocke A. Alex M. Kotzsch M. Luther T. Morgenstern E. Zieseniss S. Zahler S. Preissner K. Engelmann B. Intravascular tissue factor initiates coagulation via circulating microvesicles and platelets.FASEB J. 2003; 17: 476-8Crossref PubMed Scopus (354) Google Scholar]. Platelet TF can be released into blood as TF‐bearing circulating microvesicles upon activation by collagen and/or other stimuli [Muller et al, 2003Muller I. Klocke A. Alex M. Kotzsch M. Luther T. Morgenstern E. Zieseniss S. Zahler S. Preissner K. Engelmann B. Intravascular tissue factor initiates coagulation via circulating microvesicles and platelets.FASEB J. 2003; 17: 476-8Crossref PubMed Scopus (354) Google Scholar, Scholz et al, 2002Scholz T. Temmler U. Krause S. Heptinstall S. Losche W. Transfer of tissue factor from platelets to monocytes: role of platelet‐derived microvesicles and CD62P.Thromb Haemost. 2002; 88: 1033-8Crossref PubMed Scopus (103) Google Scholar, Siddiqui et al, 2002Siddiqui F.A. Desai H. Amirkhosravi A. Amaya M. Francis J.L. The presence and release of tissue factor from human platelets.Platelets. 2002; 13: 247-53Crossref PubMed Scopus (133) Google Scholar, Engelmann et al, 2003Engelmann B. Luther T. Muller I. Intravascular tissue factor pathway—a model for rapid initiation of coagulation within the blood vessel.Thromb Haemost. 2003; 89: 3-8Crossref PubMed Scopus (79) Google Scholar]. Elevated levels of TF‐bearing circulating microvesicles were reported in patients with aplastic anemia and Type 2 diabetes [Hugel et al, 1999Hugel B. Socie G. Vu T. Toti F. Gluckman E. Freyssinet J.M. Scrobohaci M.L. Elevated levels of circulating procoagulant microparticles in patients with paroxysmal nocturnal hemoglobinuria and aplastic anemia.Blood. 1999; 93: 3451-6Crossref PubMed Google Scholar, Diamant et al, 2002Diamant M. Nieuwland R. Pablo R.F. Sturk A. Smit J.W. Radder J.K. Elevated numbers of tissue‐factor exposing microparticles correlate with components of the metabolic syndrome in uncomplicated type 2 diabetes mellitus.Circulation. 2002; 106: 2442-7Crossref PubMed Scopus (337) Google Scholar]. Platelet‐derived TF‐bearing microvesicles can be transferred to leukocytes [Siddiqui et al, 2002Siddiqui F.A. Desai H. Amirkhosravi A. Amaya M. Francis J.L. The presence and release of tissue factor from human platelets.Platelets. 2002; 13: 247-53Crossref PubMed Scopus (133) Google Scholar], and platelet surface antigens (CD42 and CD62P) mediate these platelet‐to‐leukocyte transfers [Scholz et al, 2002Scholz T. Temmler U. Krause S. Heptinstall S. Losche W. Transfer of tissue factor from platelets to monocytes: role of platelet‐derived microvesicles and CD62P.Thromb Haemost. 2002; 88: 1033-8Crossref PubMed Scopus (103) Google Scholar]. Adhesive interactions of the TF‐bearing platelets or microvesicles to neutrophils and monocytes support the functional activation of blood‐based TF [Muller et al, 2003Muller I. Klocke A. Alex M. Kotzsch M. Luther T. Morgenstern E. Zieseniss S. Zahler S. Preissner K. Engelmann B. Intravascular tissue factor initiates coagulation via circulating microvesicles and platelets.FASEB J. 2003; 17: 476-8Crossref PubMed Scopus (354) Google Scholar, Siddiqui et al, 2002Siddiqui F.A. Desai H. Amirkhosravi A. Amaya M. Francis J.L. The presence and release of tissue factor from human platelets.Platelets. 2002; 13: 247-53Crossref PubMed Scopus (133) Google Scholar]; which is why platelet TF is a hot topic regarding its origin and function, even though there has been little evidence of de novoproduction of TF in platelets. In recent reports TF‐bearing microvesicles were indicated as being transferred from neutrophils to platelets [Diamant et al, 2002Diamant M. Nieuwland R. Pablo R.F. Sturk A. Smit J.W. Radder J.K. Elevated numbers of tissue‐factor exposing microparticles correlate with components of the metabolic syndrome in uncomplicated type 2 diabetes mellitus.Circulation. 2002; 106: 2442-7Crossref PubMed Scopus (337) Google Scholar, Rauch et al, 2000Rauch U. Bonderman D. Bohrmann B. Badimon J.J. Himber J. Riederer M.A. Nemerson Y. Transfer of tissue factor from leukocytes to platelets is mediated by CD15 and tissue factor.Blood. 2000; 96: 170-5Crossref PubMed Google Scholar, Nieuwland et al, 2000Nieuwland R. Berckmans R.J. McGregor S. Boing A.N. Romijn F.P. Westendorp R.G. Hack C.E. Sturk A. Cellular origin and procoagulant properties of microparticles in meningococcal sepsis.Blood. 2000; 95: 930-5Crossref PubMed Google Scholar]. An electronmicroscopic study suggested that TF‐positive pseudopodia extending from neutrophils contacted platelets and that CD15 and P‐selectin interactions mediated the formation of platelet aggregates containing TF microvesicles coming from the leukocytes [Rauch et al, 2000Rauch U. Bonderman D. Bohrmann B. Badimon J.J. Himber J. Riederer M.A. Nemerson Y. Transfer of tissue factor from leukocytes to platelets is mediated by CD15 and tissue factor.Blood. 2000; 96: 170-5Crossref PubMed Google Scholar]. This suggested that platelets became TF‐positive after exposure to TF‐bearing microvesicles from neutrophils. A large number of neutrophil‐derived microvesicles was observed in patient plasma; but were absent or present in only low numbers in healthy control plasma [Rauch et al, 2000Rauch U. Bonderman D. Bohrmann B. Badimon J.J. Himber J. Riederer M.A. Nemerson Y. Transfer of tissue factor from leukocytes to platelets is mediated by CD15 and tissue factor.Blood. 2000; 96: 170-5Crossref PubMed Google Scholar]. The numbers of monocyte‐ and endothelial cell‐derived microvesicles were not increased in these patients compared with controls, even though monocytes and endothelial cells are known to release TF‐exposing microvesicles in vitroupon stimulation with endotoxin [Satta et al, 1994Satta N. Toti F. Feugeas O. Bohbot A. Dachary‐Prigent J. Eschwege V. Hedman H. Freyssinet J.M. Monocyte vesiculation is a possible mechanism for dissemination of membrane‐associated procoagulant activities and adhesion molecules after stimulation by lipopolysaccharides.J Immunol. 1994; 153: 3245-55PubMed Google Scholar, Kagawa et al, 1998Kagawa H. Komiyama Y. Nakamura S. Miyake T. Miyazaki Y. Hamamoto K. Masuda M. Takahashi H. Nomura S. Fukuhara S. Expression of functional tissue factor on small vesicles of lipopolysaccharide‐stimulated human vascular endothelial cells.Thromb Res. 1998; 91: 297-304Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar]. Activated neutrophils shed receptor/components as apoptotic vesicles from cell‐surface plasma membrane during apoptosis [Moulding et al, 1999Moulding D.A. Hart C.A. Edwards S.W. Regulation of neutrophil FcgammaRIIIb (CD16) surface expression following delayed apoptosis in response to GM‐CSF and sodium butyrate.J Leukoc Biol. 1999; 65: 875-8Crossref PubMed Scopus (42) Google Scholar]. Neutrophil apoptosis, and neutrophil‐derived TF‐bearing microvesicles, were observed in in vivostudy using an LSP‐injected animal model [Higure et al, 1996Higure A. Okamoto K. Hirata K. Todoroki H. Nagafuchi Y. Takeda S. Katoh H. Itoh H. Ohsato K. Nakamura S. Macrophages and neutrophils infiltrating into the liver are responsible for tissue factor expression in a rabbit model of acute obstructive cholangitis.Thromb Haemost. 1996; 75: 791-5Crossref PubMed Scopus (50) Google Scholar]. After 1.5 h of LPS injection, TF expression was seen in accumulated neutrophils at the liver sinusoid. The cell numbers of both the accumulated and the TF‐expressing neutrophils reached a peak at the accumulated site after 3 h. TF‐expressing neutrophils markedly declined with increasing numbers of TF‐bearing microvesicles at 6 h. Interestingly, plasma TF activity increased in parallel with the increase of TF‐bearing microvesicles at the liver inflammatory site, reaching a moderate level after 3 h, and then followed a plateau after 6 h [Higure et al, 1996Higure A. Okamoto K. Hirata K. Todoroki H. Nagafuchi Y. Takeda S. Katoh H. Itoh H. Ohsato K. Nakamura S. Macrophages and neutrophils infiltrating into the liver are responsible for tissue factor expression in a rabbit model of acute obstructive cholangitis.Thromb Haemost. 1996; 75: 791-5Crossref PubMed Scopus (50) Google Scholar]. These data indicate that TF‐expressing neutrophils underwent apoptosis to produce TF‐bearing microvesicles, which are the main source of circulating TF in blood (blood‐borne TF [Giesen et al, 1999Giesen P.L. Rauch U. Bohrmann B. Kling D. Roque M. Fallon J.T. Badimon J.J. Himber J. Riederer M.A. Nemerson Y. Blood‐borne tissue factor: another view of thrombosis.Proc Natl Acad Sci USA. 1999; 96: 2311-5Crossref PubMed Scopus (921) Google Scholar]) and platelet TF; though there is some possibility of the TF‐bearing microvesicles being derived from monocytes or endothelial cells. Osterud et al. reported that neutrophils did not generate TF activity and/or antigens by in vitroexamination [Osterud et al, 2000Osterud B. Rao L.V. Olsen J.O. Induction of tissue factor expression in whole blood: lack of evidence for the presence of tissue factor expression in granulocytes.Thromb Haemost. 2000; 83: 861-7Crossref PubMed Scopus (110) Google Scholar]. Unlike monocytes, it was not easy to induce TF expression in neutrophils by in vitroexamination. Little is known about the in vitromechanism or the optimum conditions for neutrophil TF expression. Inconsistently, we detected TF mRNA in activated neutrophils that were highly purified to remove contaminating monocytes using an anti‐CD14 monoclonal antibody when ex vivoexamination was performed using whole blood incubated with LPS for 2 h (unpublished data). These controversial results could be due to unknown condition(s) or factor(s) that are critical to in vitroinduction of TF expression in neutrophils. The characteristic cell nature of neutrophils is also a plausible causative factor. Neutrophils have a very short half‐life (8–20 h) and easily undergo apoptosis, which can be enhanced several‐fold once activated by several possible stimuli. Neutrophil apoptosis is a very complicated cellular event associated with the inflammatory cytokines, interferon‐γ, granulocyte/macrophage colony‐stimulating factor (GM‐CSF), granulocyte colony‐stimulating factor (G‐CSF), tumor necrosis factor (TNF), LPS and several neutrophil components such as Fas ligand, Fas receptor, MAPK, NF‐κB, caspases, and reactive oxygen intermediates (ROI) [Akgul et al, 2001Akgul C. Moulding D.A. Edwards S.W. Molecular control of neutrophil apoptosis.FEBS Lett. 2001; 487: 318-22Crossref PubMed Scopus (410) Google Scholar, Simon, 2003Simon H.U. Neutrophil apoptosis pathways and their modifications in inflammation.Immunol Rev. 2003; 193: 101-10Crossref PubMed Scopus (303) Google Scholar], There are neutrophil subpopulations that differ in these responses and survive for much longer under cell death conditions. In an in vitrostudy using neutrophils, cell numbers and purity are also critical factors regulating activation to induce apoptotic events [Simon, 2003Simon H.U. Neutrophil apoptosis pathways and their modifications in inflammation.Immunol Rev. 2003; 193: 101-10Crossref PubMed Scopus (303) Google Scholar]. The inconsistent results regarding in vitroTF expression in neutrophils appear to have been caused by different examination conditions, numbers of cells, purity, incubation time, or stimuli. Recovery of the numbers of neutrophils markedly diminished by incubation with LPS for just 2 h, suggesting a greater loss of cell numbers during 24 h of incubation. If the non‐activated subpopulation of neutrophils could survive for a much longer period, the remaining neutrophils would be non‐activated and non‐TF expressive cells. Furthermore, platelet activating factor (PAF) appeared to be a requisite factor for in vivoTF expression in neutrophils, since preinjection of an anti‐PAF drug suppressed neutrophil TF expression [Todoroki et al, 1998Todoroki H. Higure A. Okamoto K. Okazaki K. Nagafuchi Y. Takeda S. Katoh H. Itoh H. Ohsato K. Nakamura S. Possible role of platelet‐activating factor in the in vivoexpression of tissue factor in neutrophils.J Surg Res. 1998; 80: 149-55Abstract Full Text PDF PubMed Scopus (22) Google Scholar]. The intercellular adhesion molecule‐1 (ICAM‐1) of endothelial cells was also suggested to be necessary for in vivoneutrophil TF expression [Todoroki et al, 2000Todoroki H. Nakamura S. Higure A. Okamoto K. Takeda S. Nagata N. Itoh H. Ohsato K. Neutrophils express tissue factor in a monkey model of sepsis.Surgery. 2000; 127: 209-16Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar]. However, no neutrophil TF expression was observed in vitrowhen isolated neutrophils were incubated with ICAM‐1 or selectins in the presence of LPS, PAF and/or TNF‐α. This unexpectedly complicated cellular condition may be one reason for the inconsistencies of neutrophil TF expression. Thus, we need to ascertain an optimum condition under which to examine the in vitromolecular mechanism of TF expression in neutrophils. Neutrophils are differentiated from the same common progenitor as monocytes and both have a closely related cellular nature. A possible mechanism of different gene regulation among closely related cell lineages is thought to be epigenetic events associated with the DNA methylation of promoter regions. The TF gene has typical heavy CpG islands in its promoter region [Mackman et al, 1989Mackman N. Morrissey J.H. Fowler B. Edgington T.S. Complete sequence of the human tissue factor gene, a highly regulated cellular receptor that initiates the coagulation protease cascade.Biochemistry. 1989; 28: 1755-62Crossref PubMed Scopus (167) Google Scholar]. The DNA methylation status of this CpG island of TF DNAs from neutrophils and monocytes was the same, no methylation in any CpG island of the TF gene promoter [Nakamura et al, 2003Nakamura S. Okada M. Jung‐Im H. Non‐methylated status of promoter CpG islands in human tissue factor gene.J Thromb Haemost. 2003; : OC237Google Scholar]. This indicates that the neutrophil TF gene is unlocked as monocytes, and it is highly possible that neutrophils undergo gene activation to transcribe TF mRNA. TF initiates a clotting cascade through complex formation with FVIIa, leading to subsequent activation(s) of FX and/or FIX. It was observed that FVIIa specifically bound to TF expressed on neutrophil cell surfaces [Imamura et al, 2002Imamura T. Kaneda H. Nakamura S. New functions of neutrophils in the arthus reaction: expression of tissue factor, the clotting initiator, and fibrinolysis by elastase.Lab Invest. 2002; 82: 1287-95Crossref PubMed Scopus (19) Google Scholar], indicating that TF expressed on neutrophils at inflammatory sites activates the cascade to form fibrin in vivo. In fact, fibrin deposition was observed surrounding TF‐positive neutrophils [Higure et al, 1996Higure A. Okamoto K. Hirata K. Todoroki H. Nagafuchi Y. Takeda S. Katoh H. Itoh H. Ohsato K. Nakamura S. Macrophages and neutrophils infiltrating into the liver are responsible for tissue factor expression in a rabbit model of acute obstructive cholangitis.Thromb Haemost. 1996; 75: 791-5Crossref PubMed Scopus (50) Google Scholar, Todoroki et al, 2000Todoroki H. Nakamura S. Higure A. Okamoto K. Takeda S. Nagata N. Itoh H. Ohsato K. Neutrophils express tissue factor in a monkey model of sepsis.Surgery. 2000; 127: 209-16Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar, Imamura et al, 2002Imamura T. Kaneda H. Nakamura S. New functions of neutrophils in the arthus reaction: expression of tissue factor, the clotting initiator, and fibrinolysis by elastase.Lab Invest. 2002; 82: 1287-95Crossref PubMed Scopus (19) Google Scholar]. Activated neutrophils release elastase and this lysosomal proteinase has fibrinolytic activity [Plow, 1980Plow E.F. The major fibrinolytic proteases of human leukocytes.Biochim Biophys Acta. 1980; 630: 47-56Crossref PubMed Scopus (76) Google Scholar]. Interestingly, elastase‐digested fibrin was observed surrounding the TF‐expressing neutrophils using a specific mAb (IF‐123) that distinguished elastase‐digested fibrin from plasmin‐digested fibrin [Kohno et al, 2000Kohno I. Inuzuka K. Itoh Y. Nakahara K. Eguchi Y. Sugo T. Soe G. Sakata Y. Murayama H. Matsuda M. A monoclonal antibody specific to the granulocyte‐derived elastase‐fragment D species of human fibrinogen and fibrin: its application to the measurement of granulocyte‐derived elastase digests in plasma.Blood. 2000; 95: 1721-8Crossref PubMed Google Scholar]; but little is known about the pathophysiological role of the elastase‐digested fibrin at inflammatory sites. These results suggest neutrophils have counterfunctions activating the clotting pathway by TF expression and fibrinolysis by elastase release. These cellular functions appear to be characteristic of neutrophils and differ from those of monocytes, which sustain TF‐mediated fibrin accumulation for more than 72 h at an inflammatory site in delayed hypersensitive reactivity [Imamura et al, 1993Imamura T. Iyama K. Takeya M. Kambara T. Nakamura S. Role of macrophage tissue factor in the development of the delayed hypersensitivity reaction in monkey skin.Cell Immunol. 1993; 152: 614-22Crossref PubMed Scopus (47) Google Scholar]. Neutrophils are involved in innate immunity, as are monocytes; both have characteristic functions of adhesion, spreading and/or migration that are essential to infiltrate to, or accumulate at intravascular or extravascular inflammatory sites. The biological role of TF expression in these leukocytes appears to be associated with these cellular functions. TF is known to have diverged from a common ancestor of adhesion molecules, since TF has a unique protein structure with a type III domain that is seen in the adhesion molecule family [Bazan, 1990Bazan J.F. Structural design and molecular evolution of a cytokine receptor superfamily.Proc Natl Acad Sci USA. 1990; 87: 6934-8Crossref PubMed Scopus (1886) Google Scholar]. An interesting finding of a TF function associated with cell adhesion, migration, spreading, and intracellular signaling has been reported [Ott et al, 1998Ott I. Fischer E.G. Miyagi Y. Mueller B.M. Ruf W. A role for tissue factor in cell adhesion and migration mediated by interaction with actin‐binding protein 280.J Cell Biol. 1998; 140: 1241-53Crossref PubMed Scopus (279) Google Scholar]. The TF cytoplasmic, but not the extracellular, domain appeared to be essential, and its interaction with actin‐binding protein 280 (ABP‐280) evoked these cellular functions. Electronmicroscopic study supported the contention that the ligation of cellular TF might be involved in morphogenic processes such as in cell–matrix adhesion, cell–cell contact, or cell motility by an association to cytoskeletal structures including ABP‐280 and focal adhesion kinase (FAK) [Muller et al, 1999Muller M. Albrecht S. Golfert F. Hofer A. Funk R.H. Magdolen V. Flossel C. Luther T. Localization of tissue factor in actin‐filament‐rich membrane areas of epithelial cells.Exp Cell Res. 1999; 248: 136-47Crossref PubMed Scopus (55) Google Scholar]. Another report suggested the functional implication of TF in cell–cell contacts in myocardium [Luther et al, 2000Luther T. Dittert D.D. Kotzsch M. Erlich J. Albrecht S. Mackman N. Muller M. Functional implications of tissue factor localization to cell–cell contacts in myocardium.J Pathol. 2000; 192: 121-30Crossref PubMed Scopus (34) Google Scholar]. TF might play a structural role in the maintenance of cardiac muscle, and involvement of TF in the adhesion between monocytes and endothelium was reported [Randolph et al, 1998Randolph G.J. Luther T. Albrecht S. Magdolen V. Muller W.A. Role of tissue factor in adhesion of mononuclear phagocytes to and trafficking through endothelium in vitro.Blood. 1998; 92: 4167-77Crossref PubMed Google Scholar]. Endothelial cells specifically bound to TF fragments containing cytoplasmic domains, indicating that endothelial cells bear a receptor for TF. These observations suggest that monocytes use TF, perhaps as an adhesive protein. TF was also involved in the migration of monocytes across endothelium [Muller and Randolph, 1999Muller W.A. Randolph G.J. Migration of leukocytes across endothelium and beyond: molecules involved in the transmigration and fate of monocytes.J Leukoc Biol. 1999; 66: 698-704Crossref PubMed Scopus (170) Google Scholar]. These results lead us to a tempting hypothesis that neutrophil TF has a key role in its adhesion, transmigration or cell–cell contact. In conclusion, neutrophils (polymorphonuclear leukocytes) have a function expressing TF (CD142) through genomic events. Because of its apoptotic nature, neutrophil TF appears to be a possible source of TF‐bearing circulating microvesicles, blood‐borne TF. Cell‐surface TF on neutrophils bound FVII/VIIa to initiate a clotting pathway to generate fibrin. Neutrophil TF seems to be involved in adhesion, transmigration or cell–cell contact to accumulate at inflammatory sites. We thank Drs A. Higure and H. Todoroki (Department of Surgery, University of Occupational and Environmental Health, Kitakyushu, Japan). This work was supported in part by Grants‐in‐Aids for Scientific Research (09671108) and a research grant from HS Foundation (21008).
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