LPS and Cytokine-Activated Endothelium

Angelika Bierhaus; Jiang Chen; Birgit Liliensiek; Peter P. Nawroth

doi:10.1055/s-2000-13214

Seminars in Thrombosis and Hemostasis, Table of Contents

Semin Thromb Hemost 2000; 26(5): 571-588
DOI: 10.1055/s-2000-13214

LPS and Cytokine-Activated Endothelium

Angelika Bierhaus, Jiang Chen, Birgit Liliensiek, Peter P. Nawroth

Department of Medicine IV, Section of Vascular Medicine, University of Tübingen, Tübingen, Germany

Abstract

ABSTRACT

Endothelial cells coordinate the recruitment of inflammatory cells to sites of vascular injury. Endothelial cells produce and release cytokines and growth factors serving as communication signals to leukocytes as well as with organs and tissues. In addition, endothelial cells respond to inflammatory stimuli such as lipopolysaccharides (endotoxin, LPS), cytokines, or ligation of CD40. Functional changes in response to inflammatory stimuli are mediated by induction of signaling cascades leading to activation of transcription factors and alterations in endothelial gene expression. This article summarizes the current knowledge of molecular events resulting in cytokine-mediated endothelial dysfunction.

KEYWORD

NF-κB - inflammation - TNF-α - CD40 - apoptosis

Full Text

References

REFERENCES

1 Stern D M, Bank I, Nawroth P P. Self-regulation of procoagulant events on the endothelial cell surface. J Exp Med . 1985; 162 1223-1235
2 Nawroth P P, Bank I, Handley D. Tumor necrosis factor/cachectin interacts with endothelial cell receptors to induce release of interleukin-1. J Exp Med . 1986; 163 1363-1375
3 Bevilacqua M P, Pober J S, Manjeau G R. Recombinant tumor necrosis factor induces procoagulant activity in cultured human vascular endothelium: Characterization and comparison with the action of interleukin-1. Proc Natl Acad Sci USA . 1986; 83 4533-4537
4 Pober J S. Effects of tumour necrosis factor and related cytokines on vascular endothelial cells. Ciba Found Symp . 1987; 131 170-184
5 Sieff C A, Niemeyer C M, Faller D V. Human colony-stimulating factors and stromal cell function. Soc Gen Physiol Ser . 1988; 43 47-55
6 Modat G, Dornand J, Bernad N. LPS-stimulated bovine aortic endothelial cells produce IL-1 and IL-6 like activities. Agents Actions . 1990; 30 403-411
7 Mantovani A, Bussolino F, Dejana E. Cytokine regulation of endothelial cell function. FASEB J . 1992; 6 2591-2599
8 Schonbeck U, Mach F, Bonnefoy J Y. Ligation of CD40 activates interleukin 1 beta-converting enzyme (caspase-1) activity in vascular smooth muscle and endothelial cells and promotes elaboration of active interleukin 1 beta. J Biol Chem . 1997; 272 19569-19574
9 Krishnaswamy G, Kelley J, Yerra L, Smith K J, Chi D S. Human endothelium as a source of multifunctional cytokines: Molecular regulation and possible role in human disease. J Interferon Cytokine Res . 1999; 19 91-104
10 Murdoch C, Monk P N, Finn A. Cxc chemokine receptor expression on human endothelial cells. Cytokine . 1999; 11 704-712
11 Delvos U, Janssen B, Müller-Berghaus G. Effect of lipopolysaccharides on cultured human endothelial cells. Relationship between tissue factor activity and prostacyclin release. Blut . 1987; 55 101-108
12 Henn V, Slupsky J R, Grafe M. CD40 ligand on activated platelets triggers an inflammatory reaction in endothelial cells. Nature . 1998; 391 591-594
13 Slupsky J R, Kalbas M, Willuweit A. Activated platelets induce tissue factor expression on human umbilical vein endothelial cells by ligation of CD40. Thromb Haemost . 1998; 80 1008-1014
14 Howells G, Pham P, Taylor D, Foxwell B, Feldmann M. Interleukin 4 induces interleukin 6 production by endothelial cells: Synergy with interferon-gamma. Eur J Immunol . 1991; 21 97-101
15 Romano M, Sironi M, Toniatti C. Role of IL-6 and its soluble receptor in induction of chemokines and leukocyte recruitment. Immunity . 1997; 6 315-325
16 Gerszten R E, Garcia-Zepeda E A, Lim Y C. MCP-1 and IL-8 trigger firm adhesion of monocytes to vascular endothelium under flow conditions. Nature . 1999; 39 718-723
17 Schwartz D, Andalibi A, Chaverri-Almada L. Role of the GRO family of chemokines in monocyte adhesion to MM-LDL-stimulated endothelium. J Clin Invest . 1994; 94 1968-1973
18 Ranta V, Orpana A, Carpen O. Human vascular endothelial cells produce tumor necrosis factor-α in response to proinflammatory cytokine stimulation. Crit Care Med . 1999; 27 2184-2187
19 Sironi M, Breviario F, Proserpio P. IL-1 stimulates IL-6 production in endothelial cells. Immunology . 1989; 142 549-553
20 Yue T L, Ni J, Romanic A M. TL-1, a novel tumor necrosis factor-like cytokine, induces apoptosis in endothelial cells. Involvement of activation of stress protein kinases (stress-activated protein kinase and p38 mitogen-activated protein kinase and caspase-3-like-protease). J Biol Chem . 1999; 274 1479-1486
21 Zhai Y, Ni J, Jiang G W. VEGI, a novel cytokine of the tumor necrosis family is an angiogenesis inhibitor that suppresses the growth of colon carcinoma in vivo. FASEB J . 1999; 13 181-189
22 Baeuerle P A, Baichwal V R. NF-κB as frequent target for immunosuppressive and antiinflammatory molecules. Adv Immunol . 1997; 65 111-137
23 Barnes P J, Karin M. Nuclear factor-κB: A pivotal transcription factor in chronic inflammatory diseases. N Engl J Med . 1997; 336 1066-1071
24 Thurberg B L, Collins T. The nuclear factor-κB/inhibitor of kappa B autoregulatory system and atherosclerosis. Curr Opin Lipid . 1998; 9 387-396
25 Baeuerle P A. Proinflammatory signaling: Last pieces in the NF-κB puzzle?. Curr Biol . 1998; 8 R19-R22
26 Baeuerle P A, Baltimore D. NF-κB: Ten years after. Cell . 1996; 87 13-20
27 Baeuerle P A, Henkel T. Function and activation of NF-κB in the immune system. Annu Rev Immunol . 1994; 12 141-179
28 Read M A, Whitley M Z, Williams A J, Collins T. NF-kappa B and I kappa B alpha: An inducible regulatory system in endothelial activation. J Exp Med . 1994; 179 503-512
29 Collins T, Read M, Neish A. Transcriptional regulation of endothelial adhesion molecules: NF-κB and cytokine-inducible enhancers. FASEB J . 1995; 9 899-909
30 Bierhaus A, Zhang Y, Deng Y. Mechanism of the TNFα mediated induction of endothelial tissue factor. J Biol Chem . 1995; 270 26419-26432
31 Introna M, Mantovani A. Early activation signals in endothelial cells: Stimulation by cytokines. Arterioscler Thromb Vasc Biol . 1997; 17 423-428
32 Schuhmann R R, Leong S R, Flaggs G W. Structure and function of lipopolysaccharide binding protein. Science . 1990; 249 1429-1431
33 Wright S D, Ramos R A, Tobias P S, Ulevitch R J, Mathison C D. CD14, a receptor for complexes of lipopolysaccharides (LPS) and LPS binding protein. Science . 1990; 249 1431-1433
34 Durieux J J, Vita N, Opescu O. The two soluble forms of the lipopolysaccharide receptor, CD14: Characterization and release by normal human monocytes. Eur J Immunol . 1994; 24 2006-2012
35 Pugin J, Ulevitch R J, Tobias P S. A critical role of monocytes and CD 14 in endotoxin-induced endothelial cell activation. J Exp Med . 1993; 178 2193-2200
36 Read M A, Cordle S R, Veach R A, Carlisle C D, Hawiger J. Cell-free pool of CD14 mediates activation of transcription factor NF-κB by lipopolysaccharide in human endothelial cells. Proc Natl Acad Sci USA . 1993; 90 9887-9891
37 Ulevitch R J, Tobias P S. Recognition of endotoxin by cells leading to transmembrane signaling. Curr Opin Immunol . 1994; 6 125-129
38 Noel Jr F R, Sato T T, Mendez C, Johnson M C, Pohlmann T H. Activation of human endothelial cells by viable or heat-killed gram-negative bacteria requires soluble CD14. Infect Immunol . 1995; 63 4046-4053
39 Pugin J, Ulevitch R J, Tobias P S. Activation of endothelial cells by endotoxin: Direct versus indirect pathways and the role of CD14. Prog Clin Biol Res . 1995; 392 369-373
40 Pugin J, Ulevitch R J, Tobias P S. Tumor necrosis factor-alpha and interleukin-1 beta mediate human endothelial cell activation in blood at low endotoxin concentrations. J Inflamm . 1995; 45 49-55
41 Golenbock D T, Bach R R, Lichenstein H. Soluble CD14 promotes LPS activation of CD14-deficient PNH monocytes and endothelial cells. J Lab Clin Med . 1995; 125 662-671
42 Arditi M, Zhou J. Differential antibiotic-induced endotoxin release and interleukin-6 production by human umbilical vein endothelial cells (HUVECs): Amplification of the response by coincubation of HUVEC and blood cells. J Infect Dis . 1997; 175 1255-1258
43 Arditi M, Zhou J, Torres. Lipopolysaccharide stimulates the tyrosine phosphorylation of mitogen-activated protein kinases p44, p42 and p41 in vascular endothelial cells in a soluble CD14-dependent manner. J Immunol . 1995; 155 3994-4003
44 Arditi M, Zhou J, Dorio R. Endotoxin-mediated endothelial cell injury and activation: role of soluble CD14. Infect Immunol . 1993; 61 3149-3156
45 Herrera-Velit P, Knutson K L, Reiner N E. Phosphatidylinositol 3-kinase-dependent activation of protein kinase c-zeta in bacterial lipopolysaccharide-treated human monocytes. J Biol Chem . 1997; 272 16445-16452
46 MacKichan M L, DeFranco A L. Role of ceramide in lipopolysaccharide (LPS)-induced signaling. LPS increases ceramide rather than acting as a structural homolog. J Biol Chem . 1999; 274 1767-1775
47 Zhang F X, Kirschning C J, Mancinelli R. Bacterial lipopolysaccharide activates nuclear factor-kappa B through interleukin-1 signaling mediators in cultured human dermal endothelial cells and mononuclear phagocytes. J Biol Chem . 1999; 274 7611-7614
48 Delude R L, Savedra Jr R, Zhao H. CD14 enhances cellular response to endotoxin without imparting ligand-specific recognition. Proc Natl Acad Sci USA . 1995; 92 9288-9292
49 Ingalls R R, Golenbock D T. CD11c/CD18, a transmembrane signaling receptor for lipopolysaccharide. J Exp Med . 1995; 181 1473-1479
50 Mukaida N, Ishikawa Y, Ikeda N. Novel insights into molecular mechanism of endotoxin shock: Biochemical analysis of LPS receptor signaling in a cell-free system targeting NF-κB and regulation of cytokine production through beta2 integrin in vivo. J Leukoc Biol . 1996; 59 145-151
51 Ingalls R R, Arnaout M A, Golenbock D T. Outside-in signaling by lipopolysaccharide through a tail-less integrin. J Immunol . 1997; 159 433-439
52 Ingalls R R, Monks B G, Savedra Jr R. CD11/CD18 and CD14 share a common lipid A signaling pathway. J Immunol . 1998; 161 5413-5420
53 Haziot A, Katz I, Rong G W. Evidence that the receptor for soluble CD14:LPS complexes may not be the putative signal-transducing molecule associated with membrane-bound CD14. Scand J Immunol . 1997; 46 242-245
54 Kirschning C J, Wesche H, Merrill Ayres T, Rothe M. Human toll-like receptor 2 confers responsiveness to bacterial lipopolysaccharide. J Exp Med . 1998; 188 2091-2097
55 Yang R B, Mark M R, Gurney A L, Godowski P J. Signaling events induced by lipopolysaccharide-activated toll-like receptor 2. J Immunol . 1999; 163 639-643
56 Lomaga M A, Yeh W C, Sarosi I. TRAF6 deficiency results in osteopetrosis and defective interleukin-1, CD40, and LPS signaling. Genes Dev . 1999; 13 1015-1024
57 Joseph C K, Wright S D, Bornmann W G. Bacterial lipopolysaccharide has structural similarity to ceramide and stimulates ceramide-activated protein kinase in myeloid cells. J Biol Chem . 1994; 269 17606-17611
58 de-Martin R, Vanhove B, Cheng Q. Cytokine-inducible expression in endothelial cells of an I kappa B alpha-like gene is regulated by NF kappa B. EMBO J . 1993; 12 2773-2779
59 Zabel U, Henkel T, Silva M S, Baeuerle P A. Nuclear uptake control of NF-kappa B by MAD-3, an I kappa B protein present in the nucleus. EMBO J . 1993; 12 201-211
60 Böhrer H, Qiu F, Zimmermann T. Role of NF-κB in the mortality of sepsis. J Clin Invest . 1997; 100 972-985
61 Bannerman D D, Sathyamoorthy M, Goldblum S E. Bacterial lipopolysaccharide disrupts endothelial monolayer integrity and survival signaling events through caspase cleavage of adherens junction proteins. J Biol Chem . 1998; 273 35371-35380
62 Bannerman D D, Goldblum S E. Direct effects of endotoxin on the endothelium: barrier function and injury. Lab Invest . 1999; 79 1118-1199
63 Wang J H, Redmont H P, Watson R W, Bouchier-Hayes D. Induction of human endothelial cell apoptosis requires both heat shock and oxidative stress responses. Am J Physiol . 1997; 272 C1543-C1551
64 Koide N, Abe K, Narita K. Apoptotic cell death of vascular endothelial cells and renal tubular cells in the generalized Shwartzman reaction. FEMS Immunol Med Microbiol . 1996; 16 205-211
65 Messmer U K, Briner V A, Pfeilschifter J. Tumor necrosis factor-alpha and lipopolysaccharide induce apoptotic cell death in bovine glomerular endothelial cells. Kidney Int . 1999; 55 232-2337
66 Pohlmann T H, Harlan J M. Human endothelial cell response to lipopolysaccharide, interleukin-1 and tumor necrosis factor is regulated by protein synthesis. Cell Immunol . 1989; 119 41-52
67 Marx P T, Mulder A B, Van Den Bergh A F. Apoptosis inducers endotoxin and Fas-ligation enhance the expression of vascular endothelial growth factor in human endothelial cells. Endothelium . 1999; 6 335-340
68 Choi K B, Wong F, Harlan J M. Lipopolysaccharide mediates endothelial apoptosis by a FADD-dependent pathway. J Biol Chem . 1998; 273 20185-20188
69 Beutler B, Cerami A. Cachectin and tumour necrosis factor as two sides of the same biological coin. Nature . 1986; 320 584-588
70 Boillot A, Capellier G, Racadot E. Pilot clinical trial of an anti-TNF alpha monoclonal antibody for the treatment of septic shock. Clin Intensive Care . 1995; 6 52-56
71 Van Zee K, Moldawer L, Oldenburg H. Protection against lethal Escherichia coli bacteremia in baboons (Papio anubis) by pretreatment with a 55-kD TNF receptor (CD120a)-Ig fusion protein, Ro 45-2081. J Immunol . 1996; 156 2221-2230
72 Russel D A, Tucker K K, Chinookoswong N, Thompson R C, Kohno T. Combined inhibition of interleukin-1 and tumor necrosis factor in rodent endotoxemia: improved survival and organ function. J Infect Dis . 1995; 171 1528-1538
73 Pfeffer K, Matsuyama T, Kundig T M. Mice deficient for the 55 kd tumor necrosis factor receptor are resistant to endotoxic shock, yet succumb to L. monocytogenes infection. Cell . 1993; 73 457-467
74 Rothe J, Lesslauer H, Lotscher Y. Mice lacking the tumour necrosis factor receptor 1 are resistant to TNF-mediated toxicity, but highly susceptible to infection by Listeria monocytogenes. Nature . 1993; 364 798-802
75 Eigler A, Sinha B, Hartmann G, Endres S. Taming TNF: Strategies to restrain the proinflammatory cytokine. Immunol Today . 1997; 18 487-492
76 Tewari M, Dixit V. Recent advances in tumor necrosis factor and CD40 signaling. Curr Opin Genet Dev . 1996; 6 39-44
77 Grell M, Douni E, Wajant H. The transmembrane form of tumor necrosis factor is the prime activating ligand of the 80 kDa tumor necrosis factor receptor. Cell . 1995; 83 793-802
78 Haas E, Grell M, Wajant H, Scheurich P. Continuous autotropic signaling by membrane-expressed tumor necrosis factor. J Biol Chem . 1999; 274 18107-18112
79 Rothe M, Sarma V, Dixit V M, Goeddel D V. TRAF2-mediated activation of NF-kappa B by TNF receptor 2 and CD40. Science . 1995; 269 1424-1427
80 Shu H B, Takeuchi M, Goeddel D V. The tumor necrosis factor receptor 2 signal transducers TRAF2 and c-IAP1 are components of the tumor necrosis factor receptor 1 signaling complex. Proc Natl Acad Sci USA . 1996; 93 13973-13978
81 Declercq W, Denecker G, Fiers W, Vandenabeele P. Cooperation of both TNF receptors in inducing apoptosis: Involvement of the TNF receptor-associated factor binding domain of the TNF receptor 75. Immunology . 1998; 161 390-399
82 Mercurio F, Zhu H, Murray B W. IκK-1 and IκK-2: Cytokine activated IκB kinases essential for NF-κB activation. Science . 1997; 278 860-866
83 Bennett B L, Lacson R G, Chen C C. Identification of signal-induced IκBα-kinases in human endothelial cells. J Biol Chem . 1996; 271 19680-19688
84 Cohen L, Henzel W J, Baeuerle P A. IKAP is a scaffold protein of the IkappaB kinase complex. Nature . 1998; 395 292-296
85 Rothwarf D M, Zandl E, Natoli G, Karin M. IKK-gamma is an essential regulatory subunit of the IkappaB kinase complex. Nature . 1998; 395 297-300
86 Scheidereit C. Docking IκB kinases. Nature . 1998; 395 225-226
87 Read M A, Neish A S, Luscinskas F W. The proteasome pathway is required for cytokine-induced endothelial-leukocyte adhesion molecule expression. Immunity . 1995; 2 493-506
88 Johnson D R, Douglas A, Jahnke J, Ghosh S, Pober J S. A sustained reduction in IκB-β may contribute to persistent NF-κB activation in human endothelial cells. J Biol Chem . 1996; 271 16317-16322
89 Suyang H, Phillips H R, Douglas I, Ghosh S. Role of unphosphorylated, newly synthesized IκBβ in persistent activation of NF-κB. Mol Cell Biol . 1996; 16 5444-5449
90 Modur V, Zimmerman G A, Prescott S M, McIntyre T M. Endothelial cell inflammatory response to TNFα: Ceramide-dependent and independent mitogen activated protein kinase cascades. J Biol Chem . 1996; 271 13094-13102
91 Mantovani A, Sozzani S, Vecci A, Introna M, Allavena P. Cytokine activation of endothelial cells: New molecules for an old paradigm. Thromb Haemost . 1997; 78 406-414
92 Karin M. The regulation of AP-1 activity by mitogen-activated protein kinases. J Biol Chem . 1995; 270 16483-16486
93 Karin M, Delhase M. JNK or IKK, AP-1 or NF-κB, which are the targets for MEK kinase 1 action?. Proc Natl Acad Sci USA . 1998; 95 9067-9069
94 Angel P E, Karin M. The role of jun, Fos and the AP-1 complex in cell proliferation and transformation. Biochem Biophys Res Commun . 1991; 1072 129-157
95 Kaszubska W, Hooft von Huijsduijnen R, Ghersa P. Cyclic AMP-independent ATF family members interact with NF-κB and function in the activation of the E-selectin promoter in response to cytokines . Mol Cell Biol . 1993; 13 7180-7190
96 Haimovitz-Friedman A, Cordon-Cardo C, Bayoumy S. Lipopolysaccharide induces disseminated endothelial apoptosis requiring ceramide generation. J Exp Med . 1997; 186 1831-1841
97 Chinnayaian A M, O'Rourke K, Tewari M, Dixit V. FADD, a novel death domain-containing protein interacts with the death domain of Fas and initiates apoptosis. Cell . 1995; 81 501-512
98 Hsu H, Shu H B, Pan M G, Goeddel D V. TRADD-TRAF2 and TRADD-FADD interactions define two distinct TNF receptor-1 signal transduction pathways. Cell . 1996; 84 299-308
99 Pober J S. Activation and injury of endothelial cells by cytokines. Pathol Biol (Paris) . 1998; 46 159-163
100 Fuks Z, Persaud A, Alfieri A. Basic fibroblast growth factor protects endothelial cells against radiation-induced programmed cell death in vitro and in vivo. Cancer Res . 1994; 54 2582-2590
101 Reul R M, Fang J C, Denton M D. CD40 and CD40 ligand (CD154) are coexpressed on microvessels in vivo in human cardiac allograft rejection. Transplantation . 1997; 64 1765-1774
102 Mach F, Schonbeck U, Sukhova G K. Functional CD40 ligand is expressed on human vascular endothelial cells, smooth muscle cells, and macrophages: Implications for CD40-CD40 ligand signaling in atherosclerosis. Proc Natl Acad Sci USA . 1997; 94 1931-1936
103 Mach F, Schonbeck U, Libby P. CD40 signalling in vascular cells: A key role in atherosclerosis?. Atherosclerosis . 1998; 137(Suppl) S89-S95
104 Yellin M J, Brett J, Baum D. Functional interactions of T cells with endothelial cells: The role of CD40L-CD40-mediated signals. J Exp Med . 1995; 182 1857-1864
105 Zhou L, Stordeur P, de Lavareille A. CD40 engagement on endothelial cells promotes tissue factor dependent procoagulant activity. Thromb Haemost . 1998; 79 1025-1028
106 Hollenbaugh D, Mischel Petty N, Edwards C P. Expression of functional CD40 by vascular endothelial cells. J Exp Med . 1995; 182 33-40
107 Krzesz R, Wagner A, Cattaruzza M, Hecke, M. Cytokine-inducible CD40 gene expression in vascular smooth muscle cells is mediated by nuclear factor κB and signal transducer and activator of transcription-1. FEBS Lett . 1999; 453 191-196
108 Dufay N, Reboul A, Touraine-Moulin F, Belin M F, Giraudon P. Soluble factors, including TNFα, secreted by human T cells are both cytotoxic and cytostatic for medulloblastoma cells. J Neurooncol . 1999; 43 115-126
109 Murakami K, Ma W, Fuleihan R, Pober J S. Human endothelial cells augment early CD40 ligand expression in activated CD4⁺ T cells through LFA-3-mediated stabilization of mRNA. J Immunol . 1999; 163 2667-2673
110 Pober J S. Immunobiology of human vascular endothelium. Immunol Res . 1999; 19 225-232
111 Lee H H, Dempsey P, Parks T P. Specificities of CD40 signaling: Involvement of TRAF2 in CD40 induced NF-κB activation and intercellular adhesion molecule-1 up-regulation. Proc Natl Acad Sci USA . 1999; 96 1421-1426
112 Tsukamoto N, Kobayashi N, Azuma S, Yamamoto T, Inoue J-I. Two differently regulated nuclear factor κB activation pathways triggered by the cytoplasmic tail of CD40. Proc Natl Acad Sci USA . 1999; 96 1234-1239
113 Snapper C M, Rosas F, Moorman M A. IFN-gamma is a potent inducer of Ig secretion by sort-purified murine B cells activated through the mIg, but not the CD40, signaling pathway. Int Immunol . 1996; 8 877-885
114 Chaudhuri A, Orme S, Vo T, Wang W, Cherayil B J. Phosphorylation of TRAF2 inhibits binding to the CD40 cytoplasmic domain. Biochem Biophys Res Commun . 1999; 256 620-625
115 Pullen S S, Dang T T, Crute J J, Kehry M R. CD40 signaling through tumor necrosis factor receptor-associated factors (TRAFs). Binding site specificity and activation of downstream pathways by distinct TRAFs. J Biol Chem . 1999; 274 14246-14254
116 Sutherland C L, Krebs D L, Gold M R. An 11-amino acid sequence in the cytoplasmic domain of CD40 is sufficient for activation of c-Jun N-terminal kinase, activation of MAPKAP kinase-2, phosphorylation of I kappa B alpha, and protection of EEHI-231 cells from anti-IgM-induced growth arrest. J Immunol . 1999; 162 4720-4730
117 Leo E, Welsh K, Matsutawa S. Differential requirements for tumor necrosis factor receptor-associated factor family proteins in CD40-mediated induction of NF-κB and Jun N-terminal kinase activation. J Biol Chem. 1999; 274 22414-22422
118 Karmann K, Min W, Fanslow W C, Pober J S. Activation and homologous desensitization of human endothelial cells by CD40 ligand, tumor necrosis factor and interleukin-1. J Exp Med . 1996; 184 173-182
119 Neurath M F, Pettersson S, Meyer zum Büschenfelde K H, Strober W. Local administration of antisense phosphorothioate oligonucleotides to the p65 subunit of NF-kappa B abrogates established experimental colitis in mice. Nature Med . 1996; 2 998-100
120 Schreiber S, Nikolaus S, Hampe J. Activation of nuclear factor kappa B inflammatory bowel disease. Gut . 1998; 42 477-484
121 Thiele K, Bierhaus A, Autschbach F. Cell specific effects of glucocorticoid treatment on the NF-κBp65/IκBα system in patients with Crohn's disease. Gut . 1999; 45 693-704
122 Battaglia E, Biancone L, Resegotti A. Expression of CD40 and its ligand, CD40L, in intestinal lesions of Crohn's disease. Am J Gastroenterol . 1999; 94 3279-3284
123 Bussolino F, Camussi G, Tetta C. Selected cytokines promote the synthesis of platelet-activating factor in vascular endothelial cells: Comparison between tumor necrosis factor alpha and beta and interleukin-1. J Lipid Mediat . 1990; 2 S15-S22
124 Koltai M, Hosford D, Braquet P. Role of PAF and cytokines in microvascular tissue injury. J Lab Clin Med . 1992; 119 461-466
125 Andrews R K, Shen Y, Gardiner E E. The glycoprotein Ib-IX-V-complex in platelet adhesion and signaling. Thromb Haemost . 1999; 82 357-364
126 Rock G, Wells P. New concepts in coagulation. Crit Rev Clin Lab Sci . 1997; 34 475-501
127 May A E, Neumann F J, Preissner K T. The relevance of blood cell-vessel wall adhesive interactions for vascular thrombotic disease. Thromb Haemost . 1999; 82 962-970
128 Miller D L, Yaron R, Yellin M J. CD40L-CD40 interactions regulate endothelial cell surface tissue factor and thrombomodulin. J Leukoc Biol . 1998; 63 373-379
129 Bevilacqua M P, Gimbrone Jr A M. Inducible endothelial functions in inflammation and coagulation. Semin Thromb Hemost . 1987; 13 425-433
130 Bevilacqua M P, Stengelin S, Gimbrone M A, Seed B. Endothelial leukocyte adhesion molecule 1: An inducible receptor for neutrophils related to complement regulatory proteins and lectins. Science . 1989; 243 1160-1165
131 Elices M, Osborn L, Takada Y. VCAM-1 on activated endothelium interacts with the leukocyte integrin VLA-4 at a site distinct from the VLA-4 fibronectin binding site. Cell . 1990; 60 577-584
132 Neish A S, Read M A, Thanos D. Endothelial interferon regulatory factor 1 cooperates with NF-κB as a transcriptional activator of vascular adhesion molecule 1. Mol Cell Biol . 1995; 15 2558-2569
133 Fan S T, Edgington T S. Coupling of the adhesive receptor CD11b/CD18 to functional enhancement of the effector macrophage tissue factor response. J Clin Invest . 1991; 87 50-57
134 Fan S T, Mackman N, Cui M Z, Edgington T. Integrin regulation of an inflammatory effector gene. Direct induction of the tissue factor promoter by engagement of β₁ or α₄ integrin chains. J Immunol . 1995; 154 3266-3274
135 Nawroth P P, Stern D M. Modulation of endothelial cell hemostatic properties by tumor necrosis factor. J Exp Med . 1986; 163 740-745
136 Nawroth P P, Handley D A, Esmon C T, Stern D M. Interleukin 1 induces endothelial cell procoagulant while suppressing cell-surface anticoagulant activity. Proc Natl Acad Sci USA . 1986; 83 3460-3464
137 Bach R R. Initiation of coagulation by tissue factor. Crit Rev Biochem . 1988; 23 339-348
138 Conway E M, Bach R, Rosenberg R, Konigsberg W H. Tumor necrosis factor enhances expression of tissue factor mRNA in endothelial cells. Thromb Res . 1989; 53 231-241
139 Camerer E, Kolsto A B, Prydz H. Cell biology of tissue factor, the principal initiator of blood coagulation. Thromb Res . 1996; 81 1-41
140 Moll T, Czyz M, Holzmüller H. Regulation of the tissue factor promoter in endothelial cells. J Biol Chem . 1995; 270 3849-3857
141 Bierhaus A, Hemmer C J, Mackman N. Antiparasitic treatment of patients with P. falciparum malaria reduces the ability of patient serum to induce tissue factor by decreasing NF-κB activation. Thromb Haemost . 1955; 73 39-48
142 Parry G C, Mackman N. Transcriptional regulation of tissue factor expression in human endothelial cells. Arterioscler Thromb Vasc Biol . 1995; 15 612-621
143 Mackman N. Regulation of the tissue factor gene. Thromb Haemost . 1997; 78 747-754
144 Bierhaus A, Zhang Y, Quehenberger P. The dietary pigment curcumin reduces endothelial tissue factor expression by inhibiting binding of AP-1 to the DNA and activation of NF-κB. Thromb Haemost . 1997; 77 772-782
145 Contrino J, Hair G, Kreutzer D L, Rickles F R. In situ detection of tissue factor in vascular endothelial cells: Correlation with the malignant phenotype of human breast disease. Nature Med . 1996; 2 209-215
146 Zhang Y, Deng Y, Wendt T. Intravenous somatic gene transfer with antisense tissue factor restores blood flow by reducing tumor necrosis factor induced tissue factor expression and fibrin deposition in mouse Meth-A sarcomas. J Clin Invest . 1996; 97 2213-2224
147 Zhang Y, Deng Y, Luther T. Tissue factor controls the balance of angiogenic and antiangiogenic properties of tumor cells in mice. J Clin Invest . 1994; 94 1320-1327
148 Solovey A, Gui L, Key N S, Hebbel R P. Tissue factor expression by endothelial cells in sickle cell anemia. J Clin Invest . 1998; 101 1899-1904
149 Drake T A, Cheng J, Chang A, Taylor Jr B F. Expression of tissue factor, thrombomodulin, and E-selectin in baboons with lethal Escherichia coli sepsis. Am J Pathol . 1993; 142 1458-1470
150 Warr T A, Rao L VM, Rapaport S I. Disseminated intravascular coagulation in rabbits induced by administration of LPS or tissue factor: Effect of anti-tissue factor antibodies and measurement of plasma extrinsic pathway inhibitor activity. Blood . 1990; 75 1481-1489
151 Levi M, ten Cate H, van der Poll T, van Deventer J H S. Pathogenesis of disseminated intravascular coagulation in sepsis. JAMA . 1993; 270 975-979
152 Fiedler V B, Loof I, Sander E. Monoclonal antibody to tumor necrosis factor-alpha prevents lethal endotoxin sepsis in adult rhesus monkeys. J Lab Clin Med . 1992; 120 574-588
153 Nawroth P P, Handly G, Matsueda R. Tumor necrosis factor/cachectin-induced intravascular fibrin formation in Meth A fibrosarcomas. J Exp Med . 1988; 168 637-647
154 Clauss M, Gerlach M, Gerlach H. Vascular permeability factor: A tumor derived polypeptide that induces endothelial cell and monocyte procoagulant activity and promotes monocyte migration. J Exp Med . 1990; 172 1535-1545
155 Clauss M, Murray J C, Vianna M. A polypeptide factor produced by fibrosarcoma cells that induce endothelial tissue factor and enhances the procoagulant response to tumor necrosis factor/cachectin. J Biol Chem . 1990; 265 7078-7083
156 Anrather D, Millan M T, Palmetshofer A. Thrombin activates nuclear factor-kappa B and potentiates endothelial cell activation by TNF. J Immunol . 1997; 159 5620-5628
157 Zhang Y M, Bachmann S, Hemmer C. Vascular origin of Kaposi's sarcoma. Expression of leukocyte adhesion molecule-1, thrombomodulin, and tissue factor. Am J Pathol . 1994; 144 51-59
158 Samaniego F, Markham P D, Gendelmann R, Gallo R C, Ensoli B. Inflammatory cytokines induce endothelial cells to produce and release basic fibroblast growth factor and to promote Kaposi's sarcoma-like lesions in nude mice. J Immunol . 1997; 158 1887-1894
159 von der Ahe D, Nischan C, Kunz C. Ets transcription factor binding site is required for positive and TNF alpha-induced negative promoter regulation. Nucleic Acids Res . 1993; 21 5636-5643
160 Tazawa R, Hirosawa S, Suzuki K, Hirokawa K, Aoki N J. Functional characterization of the 5′-regulatory region of the human thrombomodulin gene. Biochemistry (Tokyo) . 1993; 113 600-606
161 Hayashi T, Nakamura H, Okada A. Organization and chromosomal localization of the human endothelial protein C receptor gene. Gene . 1999; 238 367-373
162 Descheemaeker K A, Wyns S, Nelles L. Interaction of AP-1-, AP-2-, and Sp1-like proteins with two distinct sites in the upstream regulatory region of the plasminogen activator inhibitor-1 gene mediates the phorbol 12-myristate 13-acetate response. J Biol Chem. . 1992; 267 15086-15091
163 Esmon C T, Ding W, Yasuhiro K. The protein C pathway: New insights. Thromb Haemost . 1997; 78 70-74
164 Esmon C T. The roles of protein C and thrombomodulin in the regulation of blood coagulation. J Biol Chem . 1989; 264 4743-4746
165 Conway E M, Rosenberg R D. Tumor necrosis factor suppresses transcription of the thrombomodulin gene in endothelial cells. Mol Cell Biol . 1988; 8 5588-5592
166 Böhme M MJ, Deng Y, Räth U. Release of thrombomodulin from endothelial cells by a concerted action of TNFα and neutrophils: In vitro and in vivo studies. Immunology . 1996; 87 134-140
167 Esmon C T, Xu J, Gu J-M. Endothelial protein C receptor. Thromb Haemost . 1999; 82 251-258
168 Powars D, Larsen R, Johnson J. Epidemic meningococcemia and purpura fulminans with induced protein C deficiency. Clin Infect Dis . 1993; 17 254-261
169 Esmon C T, D'Angelo A, Vigano-D'Angelo S, Blick K E. Protein C prevents the coagulopathic and lethal effects of Escherichia coli infusion in the baboon. J Clin Invest . 1987; 79 918-925
170 Taylor F B, Chang A, Ruf W. E. coli septic shock is prevented by blocking tissue factor with monoclonal antibody. Circ Shock . 1991; 33 127-134
171 Hancock W W, Tsuchida A, Hau H, Thomson N M, Salem H H. The anticoagulants protein C and protein S display potent antiinflammatory and immunosuppressive effects relevant to transplant biology and therapy. Transplant Proc . 1992; 24 2302-2303
172 Hooper W C, Philipps D J, Evatt B L. Endothelial cell protein S synthesis is upregulated by the complex of IL-6 and soluble IL-6 receptor. Thromb Haemost . 1997; 77 1014-1019
173 Hooper W C, Philipps D J, Renshaw M A, Evatt B L, Benson J M. The up-regulation of IL-6 and IL-8 in human endothelial cells by activated protein C. J Immunol . 1998; 161 2567-2573
174 Levi M, ten Cate H, Bauer K A. Inhibition of LPS-induced activation of coagulation and fibrinolysis by pentoxifylline or by a monoclonal anti-tissue factor antibody in chimpanzees. J Clin Invest . 1994; 93 114-120
175 Moore K L, Andreoli S P, Esmon N, Esmon C T, Bang N U. Endotoxin enhances tissue factor and suppresses thrombomodulin expression of human vascular endothelium in vitro. J Clin Invest . 1987; 79 124-130
176 Dosne A M, Dubor F, Lutcher F, Parant M, Chedid L. Tumor necrosis factor (TNF) stimulates plasminogen activator inhibitor (PAI) production by endothelial cells and decreases blood fibrinolytic activity in the rat. Thromb Res (suppl). 1988; 8 115-122
177 Westendorp R G, Hottenga J J, Slagboom P E. Variation in plasminogen-activator-inhibitor-1 gene and risk of meningococcal septic shock. Lancet . 1999; 354 561-563
178 Gladson C L, Schleef R R, Binder B R, Loskutoff D J, Griffin J H. A comparison between activated protein C and des-1-41-light chain activated protein C in reactions with type-1 plasminogen activator inhibitor. Blood . 1989; 74 173-181
179 Hermanns P WM, Hibberd M L, Booy R. 4G/5G promoter polymorphism in the plasminogen-activator-inhibitor-1 gene and outcome of meningococcal disease. Lancet . 1999; 354 556-560
180 Lin J, Liliensiek B, Kanitz M. Molecular cloning of genes differentially regulated by TNF-α in bovine aortic endothelial cells, fibroblasts and smooth muscle cells. Cardiovasc Res . 1998; 38 802-813
181 Liliensiek B, Rocha M, Umansky V. Identification of four genes in endothelial cells whose expression is affected by tumor cells and host immune status: A study in ex vivo-isolated endothelial cells. Blood . 1998; 9 3394-3404
182 McLaughlin F, Hayes B P, Horgan C M. Tumor necrosis factor (TNF)-alpha and interleukin (IL)-1beta down-regulate intercellular adhesion molecule (ICAM)-2 expression on the endothelium. Cell Adhes Commun . 1998; 6 381-400
183 Kainulainen V, Nelimarkka L, Jarvelainen H. Suppression of syndecan-1 expression in endothelial cells by tumor necrosis factor-1. J Biol Chem . 1996; 21 18759-18766
184 Liliensiek B, Lin J, Fotsis T. Tumor necrosis factor-α controls transcription of connective tissue growth factor in cultured vascular endothelial cells. (submitted).
185 Sata M, Walsh K. TNFα regulation of Fas ligand expression on the vascular endothelium modulates leukocyte extravasation. Nature Med . 1998; 4 415-420
186 Walsh K, Sata M. Is extravasation a Fas-regulated process?. Mol Med Today . 1999; 5 61-67
187 Richardson B C, Lalwani N D, Johnson K J, Marks R M. Fas ligation triggers apoptosis in macrophages but not endothelial cells. Eur J Immunol . 1994; 24 2640-2645
188 Avanzi G C, Gallicchio M, Bottarel F. GAS6 inhibits granulocyte adhesion to endothelial cells Blood . 1998; 91 2334-2340
189 O'Donnell K, Harkes I C, Dougherty L, Wicks I P. Expression of receptor tyrosine kinase Axl and its ligand Gas6 in rheumatoid arthritis: Evidence for a novel endothelial cell survival pathway. Am J Pathol . 1999; 154 1171-1180
190 Poss K D, Tongegawa S. Heme oxygenase-1 is required for mammalian iron reutilization. Proc Natl Acad Sci USA . 1997; 94 10919-10924
191 Willis D, Moore A R, Frederick R, Willoughby D A. Heme oxygenase: A novel target for the modulation of the inflammatory response. Nature Med . 1996; 2 87-90
192 Terry C M, Clikeman J A, Hoidal J R, Callahan K S. Effect of tumor necrosis factor-alpha and interleukin-1 alpha on heme oxygenase-1 expression in human endothelial cells. Am J Physiol . 1998; 274 H883-H891
193 Yachie A, Niida Y, Wada T. Oxidative stress causes enhanced endothelial cell injury in human heme oxygenase-1 deficiency. J Clin Invest . 1999; 103 129-135
194 Kwak E L, Larochelle D A, Beaumont C, Torti S V, Torti F M. Role of NF-kappa B in the regulation of ferritin H by tumor necrosis factor-alpha. J Biol Chem . 1995; 270 15285-15293
195 Bach F H, Hancock W W, Ferran C. Protective genes expressed in endothelial cell: A regulatory response to injury. Immunol Today . 1997; 18 483-486
196 Peng H B, Libby P, Liao J K. Induction and stabilization of I kappa B alpha by nitric oxide mediates inhibition of NF-kappa B. J Biol Chem . 1995; 270 14214-14219
197 Scalia R, Booth G, Lefer D J. Vascular endothelial growth factor attenuates leukocyte-endothelium interaction during acute endothelial dysfunction: Essential role of endothelium-derived nitric oxide. FASEB J . 1999; 13 1039-1046
198 Beg A A, Baltimore D. An essential role of NF-κB in preventing TNFα-induced cell death. Science . 1996; 274 782-784
199 Soares M P, Muniappan A, Kaczmarek E. Adenovirus-mediated expression of a dominant negative mutant of p65/RelA inhibits proinflammatory gene expression in endothelial cells without sensitizing apoptosis. J Immunol . 1998; 161 4572-4582
200 Zen K, Karsan A, Stempien-Otero A. NF-κB activation is required for human endothelial cell survival during exposure to tumor necrosis factor-alpha but not to interleukin-1 beta or lipopolysaccharide. J Biol Chem . 1999; 274 28808-28815
201 Altieri D C. Paracrine control of endothelial cell survival. J Clin Invest . 1999; 104 845
202 Hu X, Yee E, Harlan J M, Wong F, Karsan A. Lipopolysaccharide induces the antiapoptotic molecules A1 and A20 in microvascular endothelial cells. Blood . 1998; 92 2759-2765
203 Cooper J T, Stroka D M, Brostjan C. A20 blocks endothelial cell activation through a NF-kappaB-dependent mechanism. J Biol Chem . 1996; 271 18068-18073
204 Xia P, Wang L, Gamble J R, Vadas M A. Activation of sphingosine kinase by tumor necrosis factor-alpha inhibits apoptosis in human endothelial cells. J Biol Chem . 1999; 274 34499-34505
205 Stehlik C, de Martin R, Kumabashiri I. Nuclear factor (NF)-kappaB-regulated X-chromosome-linked iap gene expression protects endothelial cells from tumor necrosis factor alpha-induced apoptosis. J Exp Med . 1998; 188 211-216
206 Badrichani A Z, Stroka D M, Bilbao G. Bcl-2 and Bcl-Xl serve an anti-inflammatory function in endothelial cells through inhibition of NF-κB. J Clin Invest . 1999; 103 543-553
207 Van Antwerp D, Martin S, Jafri T, Green D, Verma I. Suppression of TNFα-induced apoptosis by NF-κB. Science . 1996; 274 782-784
208 Olofsson A M, Vestberg M, Herwald H. Heparin-binding protein targeted to mitochondrial compartments protects endothelial cells from apoptosis. J Clin Invest . 1999; 104 885-894