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B Activation1
* Department of Cell Biology and Histology, Faculty of Biology, University of Murcia, Murcia, Spain; and
Research Unit, Department of Surgery, University Hospital "Virgen de la Arrixaca", Murcia, Spain
It has long been established that lower vertebrates, most notably fish and amphibians, are resistant to the toxic effect of LPS. Furthermore, the lack of a TLR4 ortholog in some fish species and the lack of the essential costimulatory molecules for LPS activation via TLR4 (i.e., myeloid differentiation protein 2 (MD-2) and CD14) in all the fish genomes and expressed sequence tag databases available led us to hypothesize that the mechanism of LPS recognition in fish may be different from that of mammals. To shed light on the role of fish TLRs in LPS recognition, a dual-luciferase reporter assay to study NF-
B activation in whole zebrafish embryos was developed and three different bony fish models were studied: 1) the gilthead seabream (Sparus aurata, Perciformes), an immunological-tractable teleost model in which the presence of a TLR4 ortholog is unknown; 2) the spotted green pufferfish (Tetraodon nigroviridis, Tetraodontiformes), which lacks a TLR4 ortholog; and 3) the zebrafish (Danio rerio, Cypriniformes), which possesses two TLR4 orthologs. Our results show that LPS signaled via a TLR4- and MyD88-independent manner in fish, and, surprisingly, that the zebrafish TLR4 orthologs negatively regulated the MyD88-dependent signaling pathway. We think that the identification of TLR4 as a negative regulator of TLR signaling in the zebrafish, together with the absence of this receptor in most fish species, explains the resistance of fish to endotoxic shock and supports the idea that the TLR4 receptor complex for LPS recognition arose after the divergence of fish and tetrapods.
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1 This work was supported by the Spanish Ministry of Education and Science (Grants BIO2005-05078 and CSD2007-00002 to V.M.), the Sixth Framework Programme of the European Union (Grant FOOD-CT-2005-007103 to V.M.), the Spanish Ministry of Health (Grant PI060369 to M.L.C.), and the University of Murcia (fellowships to F.A.-P. and A.L.-M.).
2 F.A.-P. and A.L-M. contributed equally to this work.
3 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
4 Abbreviations used in this paper: Ec, Escherichia coli; hu, human; LRR, leucine-rich repeats; MD-2, myeloid differentiation protein 2; MO, morpholino; PAMP, pathogen-associated molecular pattern; Pg, Porphyromonas gingivalis; P/S, penicillin and streptomycin; R, rough LPS; S, smooth LPS; Sa, Salmonella abortus equi; Sm, Salmonella minnesota; St, Salmonella thyphimurium; TIR, Toll/IL-1 receptor; TRIF, TIR domain-containing adapter inducing IFN-β; TRAM, TRIF-related adapter molecule; VaDNA, Vibrio anguillarum genomic DNA; zf, zebrafish.
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