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1,2
*Cell Biology and Immunology Group, Wageningen Institute of Animal Sciences, Wageningen University, Wageningen, The Netherlands;
Unit of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Brussels, Belgium, and Department of Molecular and Cellular Interactions, Institute for Biotechnology, Ghent, Belgium;
Institute for Evolution and Biodiversity, Animal Evolutionary Ecology Group, University of Münster, Münster, Germany; and
Laboratory of Biochemistry, Department of Agrotechnology and Food Sciences, Wageningen University, Wageningen, The Netherlands
Functional characterization of TNF-
in species other than mammalian vertebrates is limited, and TNF- has been studied in a limited number of fish species, primarily in vitro using recombinant proteins. Studies on TNF- from different fish species so far pointed to several inconsistencies, in particular with respect to some receptor-mediated activities of fish TNF-, such as the ability to directly activate phagocytes. In the present study a comprehensive analysis of in vitro as well as in vivo biological activities of two isoforms of carp TNF- was performed. Our results show that carp TNF- directly primes carp phagocytes and indirectly promotes typical receptor-mediated activities such as phagocyte activation by acting via endothelial cells. Additionally, for the first time in nonmammalian vertebrate species, the lectin-like activity of fish TNF- homologs was investigated. Our results show an evolutionary conservation of function of this receptor-independent activity of TNF- not only in cyprinid fish, but also in perciform and salmonid fish. The role of TNF- in vivo, during infections of carp with the blood parasite Trypanoplasma borreli, was examined using three fundamentally different but complementary approaches: (1) inhibition of TNF- expression, (2) overexpression of TNF-, and (3) inhibition of shedding of membrane-bound TNF-. Our results show that, also in fish, a tight regulation of TNF- expression is important, since depletion or excess of TNF- can make an important difference to survival of infection. Finally, we demonstrate a crucial protective role for membrane-bound TNF-, which has a yet unexploited function in fish.
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 partly supported by the European Commission’s Improving Human Potential Program under Contract HPRN-CT-2001-00214 and QLK5-CT-2001-50988 and by the European Commission through Contract FP6007103 (Improved Immunity of Aquacultured Animals, IMAQUANIM).
2 The sequence presented in this article has been submitted to GenBank under accession no. GQ231486.
3 Address correspondence and reprint requests to Dr. Geert F. Wiegertjes. Cell Biology and Immunology Group, Department of Animal Sciences, Wageningen University, P.O. Box 338, 6700 AH, Wageningen, The Netherlands. E-mail address: geert.wiegertjes{at}wur.nl
4 Abbreviations used in this paper: mTNF-, membrane-bound TNF-; cPBS, carp PBS; cRPMI, carp complete RPMI 1640 medium; DHR, dihydrorhodamine; EC, endothelial cell; EPC, Epithelioma papulosum cyprinid; HKL, head kidney leukocyte; iNOS, inducible NO synthase; LB, lysis buffer; PTX, pentoxifylline; TACE, TNF--converting enzyme.
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