Species-specific regulation of Toll-like receptor 3 genes in men and mice

Autor: Stefan W. Krause, Viola Haehnel, Michael Rehli, Sven Heinz, Mathias Müller, Marina Karaghiosoff, Lucia Schwarzfischer
Rok vydání: 2003
Předmět:
Lipopolysaccharides
Transcription
Genetic
viruses
DNA Mutational Analysis
Biochemistry
Monocytes
Mice
Interferon
Promoter Regions
Genetic
Cells
Cultured
Toll-like receptor
Membrane Glycoproteins
Reverse Transcriptase Polymerase Chain Reaction
Toll-Like Receptors
virus diseases
hemic and immune systems
Exons
Protein-Tyrosine Kinases
Up-Regulation
DNA-Binding Proteins
Tyrosine kinase 2
medicine.drug
Plasmids
Signal Transduction
DNA
Complementary
Molecular Sequence Data
chemical and pharmacologic phenomena
Receptors
Cell Surface
Biology
Transfection
Evolution
Molecular
Immune system
Species Specificity
medicine
Animals
Humans
RNA
Messenger
Molecular Biology
RNA
Double-Stranded
Cell Nucleus
TYK2 Kinase
Innate immune system
Base Sequence
Models
Genetic
Proteins
Cell Biology
DNA
Interferon-beta
Phosphoproteins
Molecular biology
Toll-Like Receptor 3
Repressor Proteins
Gene Expression Regulation
TLR3
Janus kinase
Interferon Regulatory Factor-2
Interferon regulatory factors
Interferon Regulatory Factor-1
Transcription Factors
Zdroj: The Journal of biological chemistry. 278(24)
ISSN: 0021-9258
Popis: Toll-like receptor 3 (TLR3) belongs to a family of evolutionary conserved innate immune recognition molecules and recognizes double-stranded RNA, a molecular pattern associated with viral infections. Earlier studies suggested a differential expression pattern in men and mice; the molecular basis for this observation, however, was unknown. Here we demonstrate that species-specific differences in tissue expression and responses to lipopolysaccaride (LPS) coincide with the presence of different, evolutionary non-conserved promoter sequences in both species. Despite the overall unrelatedness of TLR3 promoter sequences, mRNA expression of both TLR3 orthologues was induced by interferons, particularly by interferon (IFN)-beta. The basal and IFN-beta-induced activation of promoters from both species largely depended on similar interferon regulatory factor (IRF) elements, which constitutively bound IRF-2 and recruited IRF-1 after stimulation. In murine macrophages, IFN-beta-induced TLR3 up-regulation required IFNAR1, STAT1, and in part IRF-1, but not the Janus kinase (Jak) family member Tyk2. We also show that LPS specifically up-regulates TLR3 expression in murine cells through the induction of autocrine/paracrine IFN-beta. In humans, however, IFN-beta-induced up-regulation of TLR3 was blocked by pretreatment with LPS, despite the efficient induction of IRF-1. Our findings reveal a mechanistic basis for the observed differences as well as similarities in TLR3 expression in men and mice. The IFN-beta-TLR3 link further suggests a role of TLR3 in innate and adaptive immune responses to viral infections. It will be interesting and important to clarify whether the observed differences in the transcriptional regulation of TLR3 influence innate immune responses in a species-specific manner.
Databáze: OpenAIRE
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