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Is a Powerful Activator of Endothelial Cells but Hardly Activates Phagocytes1
* Department of Cell Biology and Histology, Faculty of Biology, University of Murcia, Murcia, Spain; and
Medical Research Council Centre for Developmental and Biomedical Genetics, University of Sheffield, Sheffield, United Kingdom
TNF-
is conserved in all vertebrate classes and has been identified in all taxonomic groups of teleost fish. However, its biological activities and its role in infection are largely unknown. Using two complementary fish models, gilthead seabream and zebrafish, we report here that the main proinflammatory effects of fish TNF- are mediated through the activation of endothelial cells. Thus, TNF- promotes the expression of E-selectin and different CC and CXC chemokines in endothelial cells, thus explaining the recruitment and activation of phagocytes observed in vivo in both species. We also found that TLR ligands, and to some extent TNF-, were able to increase the expression of MHC class II and CD83 in endothelial cells, which might suggest a role for fish endothelial cells and TNF- in Ag presentation. Lastly, we found that TNF- increases the susceptibility of the zebrafish to viral (spring viremia of carp virus) and bacterial (Streptococcus iniae) infections. Although the powerful actions of fish TNF- on endothelial cells suggest that it might facilitate pathogen dissemination, it was found that TNF- increased antiviral genes and, more importantly, had little effect on the viral load in early infection. In addition, the stimulation of ZF4 cells with TNF- resulted in increased viral replication. Together, these results indicate that fish TNF- displays different sorts of bioactivity to their mammalian counterparts and point to the complexity of the evolution that has taken place in the regulation of innate immunity by cytokines.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by the Spanish Ministry of Education and Science (Grant BIO2005-05078 to V.M.) and Fundación Séneca-Murcia and University of Murcia (fellowships to I.M. and A.L.-M., respectively).
2 Address correspondence and reprint requests to Dr. Victoriano Mulero, Department of Cell Biology and Histology, Faculty of Biology, University of Murcia, 30100 Murcia, Spain. E-mail address: vmulero{at}um.es
3 Abbreviations used in this paper: SVCV, spring viremia of carp virus; dpi, days postinfection; EEC, endocardium endothelial cell; hpi, hours postinfection; TCID50, 50% tissue culture-infective dose; sbTNF, seabream TNF-; rsbTNF, recombinant sbTNF; sRPMI, RPMI 1640 culture medium adjusted to gilthead seabream serum osmolarity (353.33 mOsm) with 0.35% NaCl; P/S, penicillin and streptomycin; VaDNA, genomic DNA from Vibrio anguillarum ATCC 19264 cells; EPC, epithelioma papulosum cyprinid cell line; PAMP, pathogen-associated molecular pattern; zfTNF, zebrafish TNF-; rzfTNF, recombinant zfTNF.
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  A. Lopez-Munoz, F. J. Roca, J. Meseguer, and V. Mulero New Insights into the Evolution of IFNs: Zebrafish Group II IFNs Induce a Rapid and Transient Expression of IFN-Dependent Genes and Display Powerful Antiviral Activities J. Immunol., March 15, 2009; 182(6): 3440 - 3449. [Abstract] [Full Text] [PDF]
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