Abstract
Background: Lactoferrin, LF, a multifunctional iron- and heparin-binding protein, present in exocrine body secretions and leukocytes, is remarkably resistant to proteolysis. Ingested bovine iron-unsaturated LF, apo-bLF, suppresses VEGF-A-mediated angiogenesis in a previously described rat mesentery angiogenesis assay, possibly explaining, at least in part, its established anticancer effect in rats and mice. Methods: Using the same experimental system, we have now studied the effect of (i) ingested human apo-LF, apo-hLF, on angiogenesis mediated by VEGF-A and bFGF, (ii) ingested human iron-saturated LF, holo-hLF, on VEGF-A-mediated angiogenesis and (iii) subcutaneous continuously infused apo-hLF on VEGF-A-mediated angiogenesis. Results: Ingested holo-hLF did not affect VEGF-A-mediated angiogenesis. Ingested apo-hLF (from one and the same batch) significantly enhanced VEGF-A-mediated angiogenesis but did not affect bFGF-mediated angiogenesis. Moreover, subcutaneously infused apo-hLF also significantly stimulated VEGF-A-mediated angiogenesis. Conclusion: Taken together, the data suggest that apo-hLF exerts a specific proangiogenic effect in VEGF-A-mediated angiogenesis. Clearly, human and bovine apo-LF exert opposite effects on VEGF-A-induced angiogenesis. Differences in molecular features between human and bovine LFs of possible significance for the outcome are discussed. In hypoxia, compensatory collateral circulation is mediated primarily by VEGF-A. We hypothesize that systemically administered apo-hLF may promote collateral blood vessel formation at hypoxic sites in normal tissue, thus counteracting ischemia and infarction.
References
1.
He J, Furmanski P: Sequence specificity and transcriptional activation in the binding of lactoferrin to DNA. Nature 1995;373:721–724.
2.
Teng CT: Lactoferrin gene expression and regulation: An overview. Biochem Cell Biol 2002;80:7–16.
3.
Lonnerdal B, Iyer S: Lactoferrin: Molecular structure and biological function. Annu Rev Nutr 1995;15:93–110.
4.
Gaudry M, Bregerie O, Andrieu V, El Benna J, Pocidalo MA, Hakim J: Intracellular pool of vascular endothelial growth factor in human neutrophils. Blood 1997;90:4153–4161.
5.
Baker EN, Anderson BF, Baker HM, MacGillivray RTA, Moore SA, Peterson NA, Shewry SC, Tweedie JW : Three-dimensional structure of lactoferrin. Implications for function, including comparisons with transferrin. Adv Exp Med Biol 1998;443:1–14.
6.
Abdallah FB, El Hage Chahine JM: Transferrins: Iron release from lactoferrin. J Mol Biol 2000;303:255–266.
7.
Shimazaki K, Tazume T, Uji K, Tanaka M, Kumura H, Mikawa K, Shimo-Oka T: Properties of a heparin-binding peptide derived from bovine lactoferrin. J Dairy Sci 1998;81:2841–2849.
8.
Kanyshkova TG, Buneva VN, Nevinsky GA: Lactoferrin and its biological functions (review). Biochemistry (Moscow) 2001;66:1–7.
9.
Baker EN, Baker HM, Kidd RD: Lactoferrin and transferrin: Functional variations on a common structural framework. Biochem Cell Biol 2002:80;27–34.
10.
Baveye S, Elass E, Mazurier J, Spik G, Legrand D: Lactoferrin: A multifunctional glycoprotein involved in the modulation of the inflammatory process. Clin Chem Lab Med 1999;37:281–286.
11.
Elass E, Masson M, Mazurier J, Legrand D: Lactoferrin inhibits the lipopolysaccharide-induced expression and proteoglycan-binding ability of interleukin-8 in human endothelial cells. Infect Immun 2002;70:1860–1866.
12.
Elass-Rochard E, Roseanu A, Legrand D, Trif M, Salmon V, Motas C, Montreuil J, Spik G: Lactoferrin-lipopolysaccharide interaction: Involvement of the 28–34 loop region of human lactoferrin in the high-affinity binding to Escherichia coli 055B5 lipopolysaccharide. Biochem J 1995;312:839–845.
13.
Dionysius DA, Grieve PA, Milne JM: Forms of lactoferrin: Their antibacterial effect on enterotoxigenic Escherichia coli. J Diary Sci 1993;76:2597–2606.
14.
Moore SA, Anderson BF, Groom CR, Haridas M, Baker EN: Three-dimensional structure of diferric bovine lactoferrin at 2.8 A resolution. J Mol Biol 1997;274:222–236.
15.
Peen E, Johansson A, Engquist M, Skogh T: Hepatic and extrahepatic clearance of circulation human lactoferrin: An experimental study in rat. Eur J Haematol 1998;61:151–159.
16.
Vorland LH, Ulvatne H, Andersen J, Haukland H, Rekdal O, Svendsen JS, Gutteberg TJ: Lactoferrin of bovine origin is more active than lactoferrins of human, murine and caprine origin. Scand J Infect Dis 1998;30:513–517.
17.
Moriishi K, Inoue S, Koura M, Amano F: Inhibition of listeriolysin O-induced hemolysis by bovine lactoferrin. Biol Pharm Bull 1999;22:1167–1172.
18.
Erga KS, Peen E, Tenstad O, Reed RK: Lactoferrin and anti-lactoferrin antibodies: Effects of ironloading of lactoferrin on albumin extravasation in different tissues in rats. Acta Physiol Scand 2000;170:11–19.
19.
El Yazidi-Belkoura I, Legrand D, Nuijens J, Slomianny MC, van Berkel P, Spik G: The binding of lactoferrin to glycosaminoglycans on enterocyte-like HT29–18-C1 cells is mediated through basic residues located in the N-terminus. Biochim Biophys Acta 2001;1568:197–204.
20.
Ward PP, Uribe-Luna S, Conneely OM: Lactoferrin and host defense. Biochem Cell Biol 2002;80:95–102.
21.
Troost FJ, Steijns J, Saris WH, Brummer RJ: Gastric digestion of bovine lactoferrin in vivo in adults. J Nutr 2001;131:2101–2104.
22.
Suzuki YA, Lonnerdal B: Characterization of mammalian receptors for lectoferrin. Biochem Cell Biol 2002;80:75–80.
23.
Kuwata H, Yip TT, Yamauchi K, Teraguchi S, Hayasawa H, Tomita M, Hutchens TW: The survival of ingested lactoferrin in the gastrointestinal tract of adult mice. Biochem J 1998;334:321–323.
24.
Harada E, Itoh Y, Sitizyo K, Takeuchi T, Araki Y, Kitagawa H: Characteristic transport of lactoferrin from the intestinal lumen into the bile via the blood in piglets. Comp Biochem Physiol A 1999;124:321–327.
25.
Håversen L, Engberg I, Baltzer L, Dolphin G, Hanson LÅ, Mattsby-Baltzer I: Human lactoferrin and peptides derived from a surface-exposed helical region reduce experimental Escherichia coli urinary tract infection in mice. Infect Immun 2000;68:5816–5823.
26.
Norrby K, Mattsby-Baltzer I, Innocenti M, Tuneberg S: Orally administered bovine lactoferrin systemically inhibits VEGF165-mediated angiogenesis in the rat. Int J Cancer 2001;91:236–240.
27.
Folkman J: Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat Med 1995;1:27–31.
28.
Bezault J, Bhimani R, Wiprovnick J, Furmanski P: Human lactoferrin inhibits growth of solid tumors and development of experimental metastases in mice. Cancer Res 1994;54:2310–2312.
29.
Sekine K, Watanabe E, Nakamura J, Takasuka N, Kim DJ, Asamoto M, Krutovskikh V, Baba-Toriyama H, Ota T, Moore MA, Masuda M, Sugimoto H, Nishino H, Kakizoe T, Tsuda H: Inhibition of azoxymethane-initiated colon tumor by bovine lactoferrin administration in F344 rats. Jpn J Cancer Res 1997;88:5223–5226.
30.
Yoo Y-C, Watanabe S, Watanabe R, Hata K, Shimazaki K, Azuma I: Bovine lactoferrin and lactoferricin, a peptide derived from bovine lactoferrin, inhibit tumor metastasis in mice. Jpn J Cancer Res 1997;88:184–190.
31.
Tsuda H, Sekine K, Nakamura J, Ushida Y, Kuhara T, Takasuka N, Kim DJ, Asamoto M, Baba-Toriyama H, Moore MA, Nishino H, Kakizoe T: Inhibition of azoxymethane initiated colon tumor and aberrant crypt foci development by bovine lactoferrin administration in F344 rats. Adv Exp Med Biol 1998;443:273–284.
32.
Ushida Y, Sekine K, Kuhara T, Takasuka N, Iigo M, Tsuda H: Inhibitory effects of bovine lactoferrin on intestinal polyposis in the ApcMin mouse. Cancer Lett 1998;134:141–145.
33.
Iigo M, Kuhara T, Ushida Y, Sekine K, Moore MA, Tsuda H: Inhibitory effect of bovine lactoferrin on colon carcinoma 26 lung metastasis in mice. Clin Exp Metastasis 1999;17:35–40.
34.
Ushida Y, Sekine K, Kuhara T, Takasuka N, Iigo M, Maeda M, Tsuda H: Possible chemopreventive effects of bovine lactoferrin on esophagus and lung carcinogenesis in the rat. Jpn J Cancer Res 1999;90:262–267.
35.
Masuda C, Wanibuchi H, Sekine K, Yano Y, Otani S, Kishimoto T, Tsuda H, Fukushima S: Chemopreventive effects of bovine lactoferrin on N-butyl-N-(4-hydroxybutyl) nitrosamine-induced rat bladder carcinogenesis. Jpn J Cancer Res 2000;91:582–588.
36.
Tanaka T, Kawabata K, Kohno H, Honjo S, Murakami M, Ota T, Tsuda H: Chemopreventive effect of bovine lactoferrin on 4-nitroquinoline 1-oxide-induced tongue carcinogenesis in male F344 rats. Jpn J Cancer Res 2000;91:25–33.
37.
Wolf JS, Li D, Taylor RJ, O’Malley BW Jr: Lactoferrin inhibits growth of malignant tumors in the head and neck. ORL 2003;65:245–249.
38.
Ivan M, Kondo K, Yang H, Kim W, Valiando J, Ohh M, Salic A, Asara JM, Lane WS, Kaelin WG: HIF alpha targeted for VHL-mediated destruction by proline hydroxylation: Implications for O2 sensing. Science 2001;292:464–468.
39.
Stein I, Keshet E: Regulation of vascular endothelial growth factor (VEGF) expression; in Voest EE, D’Amore PA (eds): Tumor Angiogenesis and Microcirculation. New York, Dekker, 2001, pp 213–226.
40.
Dvorak HF: Vascular permeability factor/vascular endothelial growth factor: A critical cytokine in tumor angiogenesis and a potential target for diagnosis and therapy. J Clin Oncol 2002;20:4368–4380.
41.
Laham RJ, Simons M: Growth factor therapy in ischemic heart disease; in Rubanyi GM (ed): Angiogenesis in Health and Disease. New York, Dekker, 2001, pp 451–475.
42.
Li WW, Jaffe M, Li VW, Tsakayannis D: Lessons to be learned from clinical trials of angiogenesis modulators in ischemic diseases; in Rubanyi GM (ed): Angiogenesis in Health and Disease. New York, Dekker, 2001, pp 519–536.
43.
Workman P, Balmain A, Hickman JA, McNally NJ, Rojas AM, Mitchison NA, et al: United Kingdom Co-Ordinating Committee on Cancer Research (UKCCCR) Guidelines for the Welfare of Animals in Experimental Neoplasia (second edition). Br J Cancer 1998;77:1–10.
44.
Norrby K: Basic fibroblast growth factor and de novo mammalian angiogenesis. Microvasc Res 1994;48:96–113.
45.
Norrby K: Vascular endothelial growth factor and de novo mammalian angiogenesis. Microvasc Res 1996;51:154–163.
46.
Yamauchi K, Toida T, Nishimura S, Nagano E, Kusuoka O, Teraguchi S, Hayasawa H, Shimamura S, Tomita M: 13-week oral repeated administration toxicity study of bovine lactoferrin in rats. Food Chem Toxicol 2000;38:503–512.
47.
Regoeczi E, Chindemi PA, Debanne MT, Prieels J-P: Lactoferrin catabolism in the rat liver. Am J Physiol 1985;248:G8–G14.
48.
Norrby K: Microvascular density in terms of number and length of microvessel segments per unit tissue volume in mammalian angiogenesis. Microvasc Res 1998;55:43–53.
49.
Näslund I, Norrby K: NO and de novo mammalian angiogenesis: Further evidence that NO inhibits bFGF-induced angiogenesis while not influencing VEGF165-induced angiogenesis. APMIS 2000;108:29–37.
50.
Norrby K: 2.5 kDa and 5.0 kDa heparin fragments specifically inhibit microvessel sprouting and network formation on VEGF165-mediated mammalian angiogenesis. Int J Exp Pathol 2000;81:191–198.
51.
Haridas M, Anderson BF, Baker HM, Norris GE, Baker EN: X-ray structural analysis of bovine lactoferrin at 2.5 A resolution. Adv Exp Med Biol 1994;357:235–238.
52.
Spik G, Legrand D, Leveugle B, Mazurier J, Mikogami T, Montreuil J, Pierce A, Rochard E: Characterization of two kinds of lactotransferrin (lactoferrin) receptors on different target cells. Adv Exp Med Biol 1994;357:13–19.
53.
Anderson BF, Baker HM, Norris GE, Rice DW, Baker EN: Structure of human lactoferrin: Crystallographic structure analysis and refinement at 2.8 A resolution. J Mol Biol 1989;209:711–734.
54.
Levay PF, Viljoen M: Lactoferrin: A general review. Haematologica 1995;80:252–267.
55.
Farnaud S, Evans RW: Lactoferrin – A multifunctional protein with antimicrobial properties. Mol Immunol 2003;40:395–405.
56.
Nibbering PH, Ravensberger E, Welling MM, van Berkel LA, van Berkel PHC, Pauwels EKJ, Nuijens JH: Human lactoferrin and peptides derived from its N terminus are highly effective against infections with antibiotica-resistant bacteria. Inf Immunol 2001;69:1469–1476.
57.
Hayashida K, Takeuchi T, Ozaki T, Shimizu H, Ando K, Miyamoto A, Harada E: Bovine lactoferrin has a nitric oxide-dependent hypotensive effect in rats. Am J Physiol Integr Comp Physiol 2004;286:R359–R365.
58.
Norrby K: Nitric oxide suppresses bFGF- and IL-1-alpha-mediated but not VEGF165-mediated angiogenesis in natively vascularized mammalian tissue. APMIS 1998;106:1142–1148.
59.
Norrby K: Constitutively synthesized nitric oxide is a physiological negative regulator of mammalian angiogenesis mediated by basic fibroblast growth factor. Int J Exp Pathol 2000;81:423–427.
60.
Norrby K: Oral administration of a nitric oxide synthase inhibitor enhances de novo mammalian angiogenesis mediated by TNF-alpha, saline and mast-cell secretion. APMIS 2000;108:496–502.
61.
Browder T, Folkman J, Pirie-Shepherd S: The hemostatic system as a regulator of angiogenesis. J Biol Chem 2000;275:1521–1524.
62.
Sala R, Jefferies WA, Walker B, Yang J, Tiong J, Law SK, Carlevaro MF, Di Marco E, Vacca A, Cancedda R, Cancedda FD, Ribatti D: The human melanoma associated protein melanotransferrin promotes endothelial cell migration and angiogenesis in vivo. Eur J Cell Biol 2002;81:599–607.
63.
Ferrara N: (2001) The role of vascular endothelial growth factor in angiogenesis; in Rubanyi GM (ed): Angiogenesis in Health and Disease. New York, Dekker, 2001, pp 399–430.
64.
Carmeliet P: VEGF gene therapy: Stimulating angiogenesis or angioma-genesis? Nat Med 2000;6:1102–1103.
65.
Ferber D: Gene therapy: Safer and virus free? Science 2001;294:1638–1642.
66.
Khan TA, Sellke FW, Laham RJ: Gene therapy progress and prospects: Therapeutic angiogenesis for limb and myocardial ischemia. Gene Ther 2003;10:285–291.
67.
Kusumanto YH, Hospers GA, Mulder NH, Tio RA: Therapeutic angiogenesis with vascular endothelial growth factor in peripheral and coronary artery disease: A review. Int J Cardiovasc Intervent 2003;5:27–34.
68.
Ozawa CR, Banfi A, Glazer NL, Thurston G, Springer ML, Kraft PE, McDonald DM, Blau HM: Microenvironmental VEGF concentration, not total dose, determines a threshold between normal and aberrant angiogenesis. J Clin Invest 2004;113:516–527.
69.
Ware JA: Too many vessels? Not enough? The wrong kind? The VEGF debate continues. Nat Med 2001;7:403–404.
70.
Dor Y, Djonov V, Keshet E: Making vascular networks in the adult: Branching morphogenesis without a roadmap. Trends Cell Biol 2003;13:131–136.
71.
Wolach B, Coates TD, Hugli TE, Baehner RL, Boxer LA: Plasma lactoferrin reflects granulocyte activation via complement in burn patients. J Lab Clin Med 1984;103:284–293.
72.
Weinberg ED: Human lactoferrin: A novel therapeutic with broad spectrum potential. J Pharm Pharmacol 2001;53:1303–1310.
73.
Choi JH, Kim HC, Lim HY, Nam DK, Kim HS, Yi JW, Chun M, Oh YT, Kang S, Park KJ, Hwang SC, Lee YH, Hahn MH: Vascular endothelial growth factor in the serum of patients with non-small cell lung cancer: Correlation with platelet and leukocyte counts. Lung Cancer 2001;33:171–179.
74.
Brock J: Lactoferrin: A multifunctional immunoregulatory protein? Immunol Today 1995;16:417–419.
75.
Damiens E, Yazidi IE, Mazurier J, Elass-Rochard E, Duthille I, Spik G, Boilly-Marer Y: Role of heparan sulphate proteoglycans in the regulation of human lactoferrin binding and activity in the MDA-MB-231 breast cancer cell line. Eur J Cell Biol 1998;77:344–351.
76.
Baveye S, Elass E, Fernig DG, Blanquart C, Mazurier J, Legrand D: Human lactoferrin interacts with soluble CD14 and inhibits expression of endothelial adhesion molecules, E-selectin and ICAM-1, induced by the CD14-lipopolysacchride complex. Infect Immun 2000;68:6519–6525.
77.
Oh S-M, Hahm DH, Kim I-H, Choi S-Y: Human neutrophil lactoferrin trans-activates the matrix metalloproteinase 1 gene through stress-activated MAPK signaling modules. J Biol Chem 2001;276:42575–42579.
78.
Eda S, Eda K, Prudhomme JG, Sherman IW: Inhibitory activity of human lactoferrin and its peptide on chondroitin sulfate A-, CD36-, and thrombospondin-mediated cytoadherence of Plasmidium falciparum-infected erythrocytes. Blood 1999;94:326–332.
79.
Willnow TE, Goldstein JL, Orth K, Brown MS, Herz J: Low-density lipoprotein receptor-related protein and gp 330 bind similar ligands, including plasminogen activator-inhibitor complexes and lactoferrin, an inhibitor of chylomicron remnant clearance. J Biol Chem 1992;267:26172–26180.
80.
Warshawsky I, Schwartz AL: The 39-kDa protein regulates LRP activity in cultured endothelial and smooth muscle cells. Eur J Cell Biol 1996;69:156–165.
81.
Vash B, Phung N, Zein S, de Camp D: Three complement-type repeats of the low-density lipoprotein receptor-related protein define a common binding for RAP, PAI-1, and lactoferrin. Blood 1998;92:3277–3285.
82.
Fillebeen C, Descamps L, Dehouck M-P, Fenart L, Benaïssa M, Spik G, Cecchelli R, Pierece A: Receptor-mediated transcytosis of lactoferrin through the blood-brain barrier. J Biol Chem 1999;274:7011–7017.
83.
Hussaini IM, Brown MD, Karns LR, Carpenter J, Redpath GT, Gonias SL, Vandenberg SR: Epidermal growth factor differentially regulates low density lipoprotein receptor-related protein gene expression in neoplastic and fetal human astrocytes. Glia 1999;25:71–84.
84.
Thornalley PJ: Cell activation by glycated proteins, AGE receptors, receptor recognition factors and functional classification of AGEs. Cell Mol Biol 1998;44:1013–1023.
85.
Schmidt AM, Hofmann M, Taguchi A, Yan SD, Stern DM: RAGE: A multiligand receptor contributing to the cellular response in diabetic vasculopathy and inflammation. Semin Thromb Hemost 2000;26:485–493.
86.
Hofmann MA, Drury S, Fu C, Qu W, Taguchi A, Avila C, Kambham N, Bierhaus A, Nawroth P, Neurath MF, Slattery T, Beach D, McClary J, Nagashima M, Moser J, Stern D, Schmidt AM: RAGE mediates a novel proinflammatory axis: A central cell surface receptor for S100/calgranulin polypetides. Cell 1999;97:889–901.
87.
Taguchi A, Blood DC, del Toro G, Canet A, Lee DC, Qu W, Tanji N, Lu Y, Lalla E, Fu C, Hofmann MA, Kislinger T, Ingram M, Lu A, Tanaka H, Hori O, Ogawa S, Astern DM, Schmidt AM: Blockade of RAGE-amphoterin signalling suppresses tumour growth and metastases. Nature 2000;405:354–360.
88.
Yonekura H, Yamamoto Y, Sakurai S, Petrova RG, Abedin MJ, Li H, Yasui K, Takeuchi M, Makita Z, Takasawa S, Okamoto H, Watanabe T, Yamamoto H: Novel splice variants of the receptor for advanced glycation end-products expressed in human vascular endothelial cells and pericytes, and their putative roles in diabetes-induced vascular injury. Biochem J 2003;370:1097–1099.
89.
van Berkel PHC, Geerts MEJ, van Veen HA, Mericskay M, de Boer HA, Nuijens JH: N-terminal stretch Arg2, Arg3, Arg4 and Arg5 of human lactoferrin is essential for binding to heparin, bacterial liposaccharide, human lysozyme and DNA. Biochem J 1997;328:145–151.
90.
Penco S, Scarfi S, Giovine M, Damonte G, Millo E, Villaggio B, Passalacqua M, Pozzolini M, Garre C, Benatti U: Identification of an important signal for, and the nuclear localization of, human lactoferrin. Biotechnol Appl Biochem 2001;34:151–159.
91.
Son K-N, Park J, Chung C-K, Chung DK, Yu D-Y, Lee K-K, Kim J: Human lactoferrin activates transcription of IL-1β gene in mammalian cells. Biochem Biophys Res Commun 2002;290:236–241.
92.
Maruyama K, Mori Y, Murasawa S, Masaki H, Takahasi N, Tsutusmi Y, Moriguchi Y, Shibazaki Y, Tanaka Y, Shibuya M, Inada M, Matsubara H, Iwasaka T: Interleukin-1 beta upregulates cardiac expression of vascular endothelial growth factor and its KDR/flk-1 via activation of protein tyrosine kinases. J Mol Cell Cardiol 1999;31:607–617.
93.
Levitas E, Chamoun D, Udoff LC, Ando M, Resnick CE, Adashi EY: Periovalutory and interleukin-1β-dependent up-regulation of intraovarian vascular endothelial growth factor (VEGF) in the rat: Potential role for VEGF in the promotion of periovalutory angiogenesis and vascular permeability. J Soc Gynecol Investig 2000;7:51–60.
94.
Bennett TA, Stetler-Stevenson WG: Matrix metalloproteinases (matrixins) and their inhibitors (TIMPs) in angiogenesis; in Rubanyi GM (ed): Angiogenesis in Health and Disease. New York, Dekker, 2001, pp 29–57.
95.
Margetts PJ, Kolb M, Yu L, Hoff CM, Holmes CJ, Anthony DC, Gauldie J: Inflammatory cytokines, angiogenesis, and fibrosis in the rat peritoneum. Am J Pathol 2002;160:2285–2294.
96.
Norrby K: Interleukin-1-alpha and de novo mammalian angiogenesis. Microvasc Res 1997;54:58–64.
97.
Wang WP, Iigo M, Sato J, Sekine K, Adachi I, Tsuda H: Activation of intestinal mucosal immunity in tumor-bearing mice by lactoferrin. Jpn J Cancer Res 2000;91:1022–1027.
98.
Angiolillo AL, Sgadari C, Taub DD, Liao F, Farber JM, Maheshwari S, Kleinman HK, Reaman GH, Tosato G: Human interferon-inducible protein 10 is a potent inhibitor of angiogenesis in vivo. J Exp Med 1995;182:155–162.
99.
Gracie JA, Robertson SE, McInnes IB: Interleukin-18. J Leukoc Biol 2003;73:213–224.
100.
Gerdes N, Sukhova GK, Libby P, Reynolds RS, Young JL, Schonbeck U: Expression of interleukin (IL)-18 and functional IL-18 receptors on human vascular endothelial cells, smooth muscle cells, and macrophages: Implications for atherogenesis. J Exp Med 2002;195:245–257.
101.
Cao R, Farnebo J, Kurimoto M, Cao Y: Interleukin-18 acts as an angiogenesis and tumor suppressor. FASEB J 1999;13:2195–2202.
102.
Park CC, Morel JC, Amin MA, Connors MA, Harlow LA, Koch AE: Evidence of IL-18 as a novel angiogenic mediator. J Immunol 2001;167:1644–1653.
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