Background Recent in-vitro studies have suggested that mast cells are involved in Dengue virus infection. To clarify the role of mast cells in the development of clinical Dengue fever, we compared the plasma levels of several mast cell-derived mediators (vascular endothelial cell growth factor [VEGF], soluble VEGF receptors [sVEGFRs], tryptase, and chymase) and -related cytokines (IL-4, -9, and -17) between patients with differing severity of Dengue fever and healthy controls. Methodology/Principal Findings The study was performed at Children's Hospital No. 2, Ho Chi Minh City, and Vinh Long Province Hospital, Vietnam from 2002 to 2005. Study patients included 103 with Dengue fever (DF), Dengue hemorrhagic fever (DHF), and Dengue shock syndrome (DSS), as diagnosed by the World Health Organization criteria. There were 189 healthy subjects, and 19 febrile illness patients of the same Kinh ethnicity. The levels of mast cell-derived mediators and -related cytokines in plasma were measured by ELISA. VEGF and sVEGFR-1 levels were significantly increased in DHF and DSS compared with those of DF and controls, whereas sVEGFR-2 levels were significantly decreased in DHF and DSS. Significant increases in tryptase and chymase levels, which were accompanied by high IL-9 and -17 concentrations, were detected in DHF and DSS patients. By day 4 of admission, VEGF, sVEGFRs, and proteases levels had returned to similar levels as DF and controls. In-vitro VEGF production by mast cells was examined in KU812 and HMC-1 cells, and was found to be highest when the cells were inoculated with Dengue virus and human Dengue virus-immune serum in the presence of IL-9. Conclusions As mast cells are an important source of VEGF, tryptase, and chymase, our findings suggest that mast cell activation and mast cell-derived mediators participate in the development of DHF. The two proteases, particularly chymase, might serve as good predictive markers of Dengue disease severity.
References
[1]
Rothman AL, Ennis FA (1994) Immunopathogenesis of dengue hemorrhagic fever. Virology 257(1): 1–6. doi: 10.1006/viro.1999.9656
[2]
Burke DS, Monath TP (2001) Flaviviruses. In: Knipe DM, Howley PM, editors. Fields virology, 4th ed., vol. 1. Philadelphia: Lippincott Williams and Wilkins. pp. 1043–1126. In.
[3]
Tseng CS, Lo HW, Teng HC, Lo WC, Ker CG (2005) Elevated levels of plasma VEGF in patients with dengue hemorrhagic fever. FEMS Immunol Med Microbiol 43: 99–102. doi: 10.1016/j.femsim.2004.10.004
[4]
Senger DR, Galli SJ, Dvorak AM, Perruzzi CA, Harvey VS, et al. (1983) Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. Science 219: 983–985. doi: 10.1126/science.6823562
[5]
Zebrowski BK, Yano S, Liu W, Shaheen RM, Hicklin DJ, et al. (1999) Vascular endothelial growth factor levels and induction of permeability in malignant pleural effusions. Clin Cancer Res 5: 3364–3368.
[6]
Leung DW, Cachianes G, Kuang WJ, Goeddel DV, Ferrara N (1989) Vascular endothelial growth factor is a secreted angiogenic mitogen. Science 246: 1306–1309. doi: 10.1126/science.2479986
[7]
Claesson-Welsh L (2003) Signal transduction by vascular endothelial growth factor receptors. Biochem Soc Trans 31: 20–24. doi: 10.1042/
[8]
Shibuya M, Ito N, Claesson-Welsh L (1999) Structure and function of vascular endothelial growth factor receptor-1 and -2. Curr Top Microbiol Immunol 237: 59–83.
[9]
Quinn TP, Peters KG, De Vries C, Ferrara N, Williams LT (1993) Fetal liver kinase 1 is a receptor for vascular endothelial growth factor and is selectively expressed in vascular endothelium. Proc Natl Acad Soci USA 90: 7533–7537. doi: 10.1073/pnas.90.16.7533
[10]
Sawano A, Iwai S, Sakurai Y, Ito M, Shitara K, et al. (2001) Flt-1, vascular endothelial growth factor receptor 1, is a novel cell surface marker for the lineage of monocyte-macrophages in humans. Blood 97: 785–791. doi: 10.1182/blood.V97.3.785
[11]
Kim I, Moon SO, Kim SH, Kim HJ, Koh YS, et al. (2001) Vascular endothelial growth factor expression of intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), and E-selectin through nuclear factor-kappa B activation in endothelial cells. J Biol Chem 276: 7614–7620. doi: 10.1074/jbc.M009705200
[12]
Reinders ME, Sho M, Izawa A, Wang P, Mukhopadhyay D, et al. (2003) Proinflammatory functions of vascular endothelial growth factor in alloimmunity. J Clin Invest 112: 1655–1665. doi: 10.1172/JCI17712
[13]
Lucerna M, Mechtcheriakova D, Kadl A, Schabbauer G, Schafer R, et al. (2003) NAB2, a corepressor of EGR-1, inhibits vascular endothelial growth factor-mediated gene induction and angiogenic responses of endothelial cells. J Biol Chem 278: 11433–11440. doi: 10.1074/jbc.M204937200
[14]
Kuenen BC, Levi M, Meijers JC, Kakkar AK, van Hinsbergh VW, et al. (2002) Analysis of coagulation cascade and endothelial cell activation during inhibition of vascular endothelial growth factor/vascular endothelial growth factor receptor pathway in cancer patients. Arterioscler Thromb Vasc Biol 22: 1500–1505. doi: 10.1161/01.ATV.0000030186.66672.36
[15]
Harada M, Mitsuyama K, Yoshida H, Sakisaka S, Taniguchi E, et al. (1998) Vascular endothelial growth factor in patients with rheumatoid arthritis. Scand J Rheumatol 27: 377–380. doi: 10.1080/03009749850154429
[16]
Taha Y, Raab Y, Larsson A, Carlson M, Loof L, et al. (2004) Vascular endothelial growth factor (VEGF)–a possible mediator of inflammation and mucosal permeability in patients with collagenous colitis. Dig Dis Sci 49: 109–115. doi: 10.1023/B:DDAS.0000011611.92440.f2
[17]
Tuchinda M, Dhorranintra , B , Tuchinda P (1977) Histamine content in 24-hour urine in patients with dengue haemorrhagic fever. Southeast Asian J Trop Med Public Health 8: 80–83.
[18]
Bhamarapravati H, Tuchinda P, Boonyapaknavik V (1967) Pathology of Thailand hemorrhagic fever: a study of 100 autopsy cases. Ann Trop Med Parasitol 61: 500–510.
[19]
King CA, Marshall JS, Alshurafa H, Anderson R (2000) Release of vasoactive cytokines by antibody-enhanced Dengue virus infection of a human mast cell/basophil line. J Virol 74: 7146–7150. doi: 10.1128/JVI.74.15.7146-7150.2000
[20]
King CA, Anderson R, Marshall JS (2002) Dengue Virus Selectively Induces Human Mast Cell Chemokine Production. J Virol 76: 8408–8419. doi: 10.1128/JVI.76.16.8408-8419.2002
Galli SJ, Kalesnikoff J, Grimbalderson MA, Piliponsky AM, Williams CT, et al. (2005) Mast cells as “tunable” effector and immunoregulatory cells: recent advances. Annu Rev Immunol 23: 749–786. doi: 10.1146/annurev.immunol.21.120601.141025
[23]
Galli SJ, Maurer M, Lantz CS (1999) Mast cells as sentinels of innate immunity. Curr Opin Immunol 11: 53–59. doi: 10.1016/S0952-7915(99)80010-7
[24]
Marshall JS, Bienenstock J (1994) The role of mast cells in inflammatory reactions of the airways, skin, and intestine. Curr Opin Immunol 6: 853–859. doi: 10.1016/0952-7915(94)90004-3
[25]
Echtenacher B, Mannel DN, Hultner L (1996) Critical protective role of mast cells in a model of acute septic peritonitis. Nature 381: 75–77. doi: 10.1038/381075a0
[26]
Church MK, Holgate ST, Shute JK, Walls AF, Sampson AP (1998) Mast cell-derived mediators. Allergy: Principles and practice, by Elliot Meddleton, 5th ed. St. Louis: Mosby.
[27]
Féger F, Varadaradjalou S, Gao Z, Abraham SN, Arock M (2002) The role of mast cells in host defense and their subversion by bacterial pathogens. Trends Immunol 23: 151–158. doi: 10.1016/S1471-4906(01)02156-1
[28]
Schwartz LB, Lewis RA, Austen KF (1981) Tryptase from human pulmonary mast cells. Purification and characterization. J Biol Chem 256: 11939–11943.
[29]
Schwartz LB, Sakai K, Bradford TR, Ren S, Zweiman B, et al. (1995) The alpha form of human tryptase is the predominant type present in blood at baseline in normal subjects and is elevated in those with systemic mastocytosis. J Clin Invest 96: 2702–2710. doi: 10.1172/JCI118337
[30]
Schwartz LB, Irani AM, Roller K, Castells MC, Schechter NM (1987) Quantitation of histamine, tryptase, and chymase in dispersed human T and TC mast cells. J Immunol 138: 2611–2615.
[31]
He S, Walls AF (1998) Human mast cell chymase induces the accumulation of neutrophils, eosinophils and other inflammatory cells in vivo. Br J Pharmacol 125: 1491–1500. doi: 10.1038/sj.bjp.0702223
[32]
Hultner L, Druez C, Moeller J, Uyttenhove C, Schmitt E, et al. (1990) Mast cell growth-enhancing activity (MEA) is structurally related and functionally identical to the mouse T cell growth factor P40/TCGFIII (interleukin 9). Eur J Immunol 20: 1413–1416. doi: 10.1002/eji.1830200632
[33]
Renauld JC, Vink A, Louahed J, Van Snick J (1995) Interleukin-9 is a major anti-apoptotic factor for thymic lymphomas. Blood 85: 1300–1305.
[34]
Nowak EC, Weaver CT, Turner H, Begum-Haque S, Becher B, et al. (2009) IL-9 as a mediator of Th17-driven inflammatory disease. J Exp Med 206: 1653–1660. doi: 10.1084/jem.20090246
[35]
World Health Organization (1997) Dengue hemorrhagic fever: diagnosis, treatment, prevention, and control. pp. 1–11. Geneva.
[36]
Rigau-Pérez JG (2006) Severe dengue: the need for new case definitions. Lancet Infect Dis 6: 297–302. doi: 10.1016/S1473-3099(06)70465-0
[37]
World Health Organization (2005) Dengue, dengue haemorrhagic fever and dengue shock syndrome in the context of the integrated management of childhood illness. WHO/FCH/CAH/05.13.
[38]
Lan NTP, Kikuchi M, Huong VTQ, Ha DQ, Thuy TT, et al. (2008) Protective and Enhancing H2LA Alleles, HLA-DRB1*0901 and HLA-A*24, for Severe Forms of Dengue Virus Infection, Dengue Hemorrhagic Fever and Dengue Shock Syndrome. PLoS Negl Trop Dis 2(10): e304. doi:10.1371/journal.pntd.0000304.
[39]
Lanciotti RS, Calisher CH, Gubler DJ, Chang GJ, Vorndam AV (1992) Rapid detection and typing of dengue viruses from clinical samples by using reverse transcriptase-polymerase chain reaction. J Clin Microbiol 30: 545–551.
[40]
Innis BL, Nisalak A, Nimmannitva S, Kusalerdchariya S, Chongswasdi V, et al. (1989) An enzyme-linked immunosorbent assay to characterize dengue infections where dengue and Japanese encephalitis co-circulate. Am J Trop Med Hyg 40: 418–427.
[41]
Gubler DJ, Kuno G, Sather GE, Valez M, Oliver A (1984) Mosquito cell cultures and specific monoclonal antibodies in surveillance for dengue viruses. Am J Trop Med Hyg 33: 158–165.
[42]
Kishi K (1985) A new leukemia cell line with Philadelphia chromosome characterized as basophil precursors. Leuk Res 9: 381–390. doi: 10.1016/0145-2126(85)90060-8
[43]
Butterfield JH, Weiler D, Dewald G, Gleich GJ (1988) Establishment of an immature mast cell line from a patient with mast cell leukemia. Leuk Res 12: 345–355. doi: 10.1016/0145-2126(88)90050-1
[44]
Igarashi A (1978) Isolation of a Singh's Aedes albopictus cell clone sensitive to dengue and chikungunya viruses. J Gen Virol 40: 531–544. doi: 10.1099/0022-1317-40-3-531
[45]
Kinoshita H, Mathenge EGM, Hung NT, Huong VTQ, Kumatori A, et al. (2009) Isolation and characterization of two phenotypically distinct Dengue type-2 virus isolate from the same Dengue hemorrhagic fever patients. Jpn J Infect Dis 62: 343–350.
[46]
Boesiger J, Tsai M, Maurer M, Yamaguchi M, Brown LF, et al. (1998) Mast cells can secrete vascular permeability factor/vascular endothelial cell growth factor and exhibit enhanced release after immunoglobulin E–dependent upregulation of Fcεreceptor I expression. J Exp Med 21: 1135–1145. doi: 10.1084/jem.188.6.1135
[47]
Grützkau A, Krüger-Krasagakes S, Baumeister H, Schwarz C, K？gel H, et al. (1998) Synthesis, storage, and release of vascular endothelial growth factor/vascular permeability factor (VEGF/VPF) by human mast cells: Implications for the biological significance of VEGF206. Mol Biol Cell 9: 875–884. doi: 10.1091/mbc.9.4.875
[48]
Srikiatkhachorn A, Ajariyakhajorn C, Endy TP, Kalayanarooj S, Libraty DH, et al. (2007) Virus-induced decline in soluble vascular endothelial growth receptor 2 is associated with plasma leakage in Dengue hemorrhagic fever. J Virol 81: 1592–1600. doi: 10.1128/JVI.01642-06
[49]
Watenberger J, Claessen-Weish L, Siegbahn A, Shibuya M, Heldin CH (1994) Different signal transduction properties of KDR and Flt-1, two receptors for vascular endothelial growth factor. J Biol Chem 269: 26988–26995.
[50]
Sathupan P, Khongphattanayothin A, Srisai J, Srikaew K, Poovorawan Y (2007) The role of vascular endothelial growth factor leading to vascular leakage in children with dengue virus infection. Ann Trop Paediatr 27: 179–84. doi: 10.1179/146532807X220280
[51]
Seet RCS, Chow AWL, Quek AML, Chen Y-H, Lim ECH (2009) Relationship between circulating vascular endothelial growth factor and its soluble receptors in adults with dengue virus infection: a case—control study. Int J Infect Dis 13: e248–e253. doi: 10.1016/j.ijid.2008.11.028
[52]
Becquart P, Wauquier N, Nkoghe D, Ndjoyi-Mbiguino A, Padilla C, et al. (2010) Acute dengue virus 2 infection in Gabonese patients is associated with an early innate immune response, including strong interferon alpha production. BMC Infect Dis 10: 356–366. doi: 10.1186/1471-2334-10-356
[53]
Ferrara N, Davis-Smyth T (1997) The biology of vascular endothelial growth factor. Endocr Rev 18: 4–25. doi: 10.1210/er.18.1.4
[54]
Dvorak HF, Brown LF, Detmar M, Dvorak AM (1995) Vascular permeability factor/vascular endothelial growth factor, microvascular hyperpermeability, and angiogenesis. Am J Pathol 146: 1029–1039.
[55]
Brown M, King CA, Sherren C, Marshall JS, Anderson R (2006) A dominant role for FcγRII in antibody-enhanced dengue virus infection of human mast cells and associated CCL5 release. J Leukoc Biol 80: 1242–1250. doi: 10.1189/jlb.0805441
[56]
Halstead SB, Mimmannitya S, Cohen SN (1970) Observations related to pathogenesis of dengue hemorrhagic fever. IV. Relation of disease severity to antibody response and virus recovered. Yale J Biol Med 42: 311–328.
[57]
Guzman MG, Kouri G (2008) Dengue haemorrhagic fever integral hypothesis: confirming observations, 1987—2007. Trans Roy Soc Trop Med Hyg 102: 522–523. doi: 10.1016/j.trstmh.2008.03.001
[58]
Koraka P, Murgue B, Deparis X, Setiati TE, Suharti C, et al. (2003) Elevated levels of total and Dengue virus-specific immunoglobulin E in patients with varying disease severity. J Med Virol 70: 91–98. doi: 10.1002/jmv.10358
[59]
Louahed J, Kermouni A, Van Snick J, Renauld JC (1995) IL-9 induces expression of granzymes and high-affinity IgE receptor in murine T helper clones. J Immunol 154: 5061–5070.
[60]
Veldhoen M, Uyttenhove C, van Snick J, Helmby H, Westendorf A, et al. (2008) Transforming growth factor-beta ‘reprograms’ the differentiation of T helper 2cells and promotes an interleukin 9-producing subset. Nat Immunol 9: 1341–1346. doi: 10.1038/ni.1659
[61]
Dardalhon V, Awasthi A, Kwon H, Galileos G, Gao W, et al. (2008) IL-4 inhibits TGF-beta induced Foxp3+ T cells and, together with TGF-beta, generates IL-9+ IL-10+ Foxp3？ effector T cells. Nat Immunol 9: 1347–1355. doi: 10.1038/ni.1677
[62]
Soroosh P, Doherty TA (2008) Th 9 and allergic disease. Immunology 127: 450–458. doi: 10.1111/j.1365-2567.2009.03114.x
[63]
Kitaura-Inenaga K, Hara M, Higuchi K, Yamamoto K, Yamaki A, et al. (2003) Gene expression of cardiac mast cell chymase and tryptase in a murine model of heart failure caused by viral myocarditis. Circ J 67: 881–884. doi: 10.1253/circj.67.881
[64]
Alho OP, Karttunen TJ, Karttunen R, Tuokko H, Koskela M, Uhari M (2003) Lymphocyte and mast cell counts are increased in the nasal mucosa in symptomatic natural colds. Clin Exp Immunol 131: 138–142. doi: 10.1046/j.1365-2249.2003.02037.x
[65]
Pejler G, Abrink M, Ringvall M, Wernersson S (2007) Mast Cell Proteases, Advances in Immunology, Volume 95:169–229. Elsevier Inc. ISSN 0065-2776, DOI: 10.1016/S0065-277.
[66]
Brown MG, Hermann LL, Issekutz AC, Marshall JS, Rowter D, Al-Afif A, Anderson1 R (2011) Dengue virus infection of mast cells triggers endothelial cell activation. J Virol 85: 1145–1115. doi: 10.1128/JVI.01630-10
[67]
St. John AL, Rathorea APS, Yap H, Ng M-L, Metcalfe DD, et al. (2011) Immune surveillance by mast cells during dengue infection promotes natural killer (NK) and NKT-cell recruitment and viral clearance. Proc Nat Acad Soc USA 108: 9190–9195. doi: 10.1016/s0065-2776(07)95006-3
