Molecular immunology
-
Molecular immunology · May 2005
Functional characterization of full-length TLR3, IRAK-4, and TRAF6 in zebrafish (Danio rerio).
Recently, the zebrafish, Danio rerio, has been recognized as a useful model for infectious disease and immunity. The Toll-like receptor (TLR) family is an evolutionarily conserved component of the innate immune system that responds to specific pathogen-associated molecular patterns (PAMPs) during an infection. This study reports the identification and characterization of a full-length orthologue of mammalian TLR3, and the key TLR pathway signaling molecules IRAK-4 and TRAF6 in the zebrafish. ⋯ Following exposure to SHRV, only zfTLR3 and zfTRAF6 mRNA transcripts were upregulated. Interestingly, exposure of fish to E. tarda resulted in an unexpected increase in mRNA expression of zfTLR3, as well as the anticipated upregulation of zfIRAK-4 and zfTRAF6 mRNA transcripts. These results demonstrate that zebrafish possess conserved TLR-signaling pathways, further emphasizing the utility of the zebrafish as a model for vertebrate immunology.
-
Molecular immunology · Jan 2004
Toll-like receptor gene family and TIR-domain adapters in Danio rerio.
The toll-like family of receptors (TLR) is an ancient pattern recognition receptor family, conserved from insects to mammals. We have identified in zebrafish (Danio rerio) 19 putative TLR variants, the orthologs of mammalian TLR2-5, 7-9, a fish specific receptor type group and three putative splice variants. One receptor is very close to mammalian TLR1, 6 and 10 and seems to be their common ancestor. ⋯ By RT-PCR we showed that all TLR are widely expressed in adult tissues, but also at different stages of development. All these TLRs contain very conserved toll/interleukin-1 receptor (TIR) domains able to interact with TIR-domain of adapter molecules. We demonstrate here that TIR-domain containing adapters MyD88 and SARM are present in zebrafish, showing that TLR adapter molecules are highly conserved in evolution.
-
Molecular immunology · Jan 2004
Expression analysis of the Toll-like receptor and TIR domain adaptor families of zebrafish.
The zebrafish genomic sequence database was analysed for the presence of genes encoding members of the Toll-like receptors (TLR) and interleukin receptors (IL-R) and associated adaptor proteins containing a TIR domain. The resulting predictions show the presence of one or more counterparts for the human TLR1, TLR2, TLR3, TLR4, TLR5, TLR7, TLR8, TLR9, IL-1R and IL-18R genes and one copy of the adaptor genes MyD88, MAL, TRIF and SARM. In contrast to data for the pufferfish Fugu rubripes, zebrafish has two genes that are highly similar to human TLR4. ⋯ Expression analysis using reverse transcriptase-PCR (RT-PCR) shows that 17 of the predicted zebrafish TLR genes and all the genes encoding adaptor proteins are expressed in the adult stage. A subset of the TLR genes are expressed at higher levels in fish infected with the pathogen Mycobacterium marinum. The induced genes include the homologues of the human TLR1 and TLR2 genes, whose functions are associated with mycobacterial infections, underscoring the suitability of zebrafish as a model for analysis of the vertebrate innate immune system.
-
Molecular immunology · Sep 2003
ReviewObstacles to cancer immunotherapy: expression of membrane complement regulatory proteins (mCRPs) in tumors.
Monoclonal antibodies (mAbs) are being increasingly used in cancer therapy owing to their ability to recognize specifically cancer cells and to activate complement- and cell-mediated cytotoxicity and/or to induce growth arrest or apoptosis. The therapeutic potential of anticancer antibodies is significantly limited due to the ability of cancer cells to block killing by complement. Of the multiple resistance strategies exploited by cancer cells, the expression of membrane complement regulatory proteins (mCRPs), such as CD46 (membrane cofactor protein (MCP)), CD55 (decay-accelerating factor (DAF)), CD35 (complement receptor type-1 (CR1)) and CD59, has received most attention. ⋯ In general, CD59 appears to be the most effective mCRP protecting tumor cells from complement-mediated lysis. Nevertheless, it acts additively, and in certain tumors even synergistically, with CD55 and CD46. It is envisaged that treatment of cancer patients with mCRP blocking antibodies targeted specifically to cancer cells in combination with anticancer complement-fixing antibodies will improve the therapeutic efficacy.