Genomic structure, promoter analysis and expression of the porcine (Sus scrofa) TLR4 gene

Thomas, Anne; Broers, Aurore D.; Vandegaart, Hélène; Desmecht, Daniël

doi:10.1016/j.molimm.2005.04.001

Cited by 32 publications

(29 citation statements)

References 21 publications

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“…31 However, notable differences exist with respect to the elements implicated in gene regulation, which may account for species differences in terms of tissue expression and modulation by different stimuli. 28,31 The LXRE site is not conserved between the human and mouse TLR-4 promoters, likely explaining the species-specific regulation of TLR-4 by LXRs. Increased expression of TLR-4 resulted in an enhanced responsiveness of human macrophages to LPS.…”

Section: Discussionmentioning

confidence: 99%

“…These data demonstrate that LXR␣ and LXR␤ bind as a heterodimer with RXR␣ to the (Ϫ477/Ϫ461) TLR-4 -LXRE present in the promoter of the human TLR-4 gene. Alignment of the human and murine TLR-4 5Ј-promoter region sequence 28 indicated that the LXRE site is not conserved between the human and the murine promoters, probably explaining the species-specific regulation of TLR-4 by LXR (Figure 2A).…”

Section: Lxrs Bind To the Human Tlr-4 Promoter In Vitro And In Vivomentioning

confidence: 99%

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Liver X Receptor Activation Potentiates the Lipopolysaccharide Response in Human Macrophages

Fontaine

Rigamonti

Nohara

et al. 2007

Circulation Research

119

128

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Abstract-Macrophages play a central role in host defense against pathogen microbes by recognizing bacterial components, resulting in the activation of an arsenal of anti-microbial effectors. Toll-like receptor (TLR)-4 mediates the recognition of lipopolysaccharide, a pathogen-associated molecular pattern from Gram-negative bacteria. Activation of the TLR-4 signaling pathway by lipopolysaccharide increases antibacterial effects by inducing secretion of cytokines that activate an immune inflammatory response and by generating bactericidal reactive oxygen species via the NADPH oxidase system. Liver X Receptors (LXRs) are nuclear receptors controlling cholesterol homeostasis and inflammation in macrophages. In addition, LXRs are critical for macrophage survival and play a role in the innate immune response in the mouse. In this study, we investigated whether LXR activation also regulates host defense mechanisms in human macrophages. In primary human macrophages, oxidized LDL and synthetic LXR ligands increased TLR-4 gene expression. Transient transfection assays, gel shift and chromatin immunoprecipitation analysis indicated that LXRs induce human TLR-4 promoter activity by binding to a DR4-type LXR response element. LXR induction of TLR-4 mRNA was followed by an induction of TLR-4 protein expression. Moreover, although short-term pretreatment with LXR agonists significantly reduced the inflammatory response induced by lipopolysaccharide, pretreatment of macrophages for 48 hours with LXR agonists resulted in an enhanced lipopolysaccharide response. Finally, LXR activation increased reactive oxygen species generation by enhancing the expression of NADPH oxidase subunits. These data provide evidence for an immunomodulatory function of LXRs in human macrophages via mechanisms distinct from those previously identified in mouse macrophages. Key Words: macrophages Ⅲ nuclear receptors Ⅲ lipopolysaccharide Ⅲ reactive oxygen species M acrophages participate in the regulation of innate and adaptive immunity. These cells play a central role in the host defense against pathogen microbes by rapidly recognizing bacterial components and activating an arsenal of antimicrobial effectors. 1 The ability of macrophages to recognize bacterial pathogen-associated molecular patterns is conferred in part by the Toll-like receptor (TLR) family of proteins. Ten members of the TLR family have been described that collectively recognize a wide range of microbial components. 2 Lipopolysaccharide (LPS) is an integral component of the outer membrane of Gram-negative bacteria. LPS signaling is mediated by TLR-4, because invalidation of this gene in mice leads to LPS-unresponsiveness. 3 LPS binding to TLR-4 activates the mitogen-activated protein kinases (MAPK) c-Jun N-terminal kinase (Jnk), p38, and extracellular signal-regulated kinase (Erk) cascades 2,4 and induces the expression of genes involved in innate immunity (eg, selectins, NADPH oxidase) and inflammatory response (eg, monocyte chemoattractant protein [MCP]-1 and tumor necrosis factor [T...

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Section: Discussionmentioning

confidence: 99%

Section: Lxrs Bind To the Human Tlr-4 Promoter In Vitro And In Vivomentioning

confidence: 99%

Liver X Receptor Activation Potentiates the Lipopolysaccharide Response in Human Macrophages

Fontaine

Rigamonti

Nohara

et al. 2007

Circulation Research

119

128

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“…In this regard, gene evolution across species can lead to different TLR4 gene expression patterns or changes in the receptor’s affinity and specificity to its ligands. Consequently, polymorphisms in the coding or promoter sequence of TLR4 in different species may lead to different resistance/susceptibility patterns to infectious diseases (10, 42). Human TLR4 gene is composed of three exons.…”

Section: Molecular Cellular and Functional Properties Of Tlr4 Acrosmentioning

confidence: 99%

A Comparative Review of Toll-Like Receptor 4 Expression and Functionality in Different Animal Species

2014

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Toll-like receptors (TLRs) belong to the pattern recognition receptor (PRR) family, a key component of the innate immune system. TLRs detect invading pathogens and initiate an immediate immune response to them, followed by a long-lasting adaptive immune response. Activation of TLRs leads to the synthesis of pro-inflammatory cytokines and chemokines and the expression of co-stimulatory molecules. TLR4 specifically recognizes bacterial lipopolysaccharide, along with several other components of pathogens and endogenous molecules produced during abnormal situations, such as tissue damage. Evolution across species can lead to substantial diversity in the TLR4’s affinity and specificity to its ligands, the TLR4 gene and cellular expression patterns and tissue distribution. Consequently, TLR4 functions vary across different species. In recent years, the use of synthetic TLR agonists as adjuvants has emerged as a realistic therapeutic goal, notably for the development of vaccines against poorly immunogenic targets. Given that an adjuvanted vaccine must be assessed in pre-clinical animal models before being tested in humans, the extent to which an animal model represents and predicts the human condition is of particular importance. This review focuses on the current knowledge on the critical points of divergence between human and the mammalian species commonly used in vaccine research and development (non-human primate, mouse, rat, rabbit, swine, and dog), in terms of molecular, cellular, and functional properties of TLR4.

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“…Existing evidence suggests that the pig TLR system may be closer to that of humans than the murine system is (Jungi et al., 2011; Vaure and Liu, 2014). Although, porcine, human and murine TLR4 promoter sequences were similar, murine TLR4 promoter exhibited significant differences in the regulation of gene expression; whereas porcine TLR4 promoter shared more common features with the human TLR4 promoter (Roger et al, 2005; Thomas et al, 2006). More studies of porcine TLR expression and function are needed to evaluate if the pig model can effectively mimic and predict human conditions and outcomes.…”

Section: Introductionmentioning

confidence: 95%

Tissue-specific mRNA expression profiles of porcine Toll-like receptors at different ages in germ-free and conventional pigs

Shao

Fischer

Kandasamy

et al. 2016

Veterinary Immunology and Immunopathology

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Toll-like receptors (TLRs), key initiators of innate immune responses, recognize antigens and are essential in linking innate and adaptive immune responses. Misrecognition and over-stimulation/expression of TLRs may contribute to the development of chronic inflammatory diseases and autoimmune diseases. However, appropriate and mature TLR responses are associated with the establishment of resistance against some infectious diseases. In this study, we assessed the mRNA expression profile of TLRs 1-10 in splenic and ileal mononuclear cells (MNCs) and dendritic cells (DCs) of germ-free (GF) and conventional pigs at different ages. We found that the TLR mRNA expression profiles were distinct between GF and conventional pigs. The expression profiles were also significantly different between splenic and ileal MNCs/DCs. Comparison of the TLR expression profiles in GF and conventional newborn and young pigs demonstrated that exposure to commensal microbiota may play a more important role than age in TLR mRNA expression profiles. To our knowledge, this is the first report that systematically assesses porcine TLRs 1-10 mRNA expression profiles in MNCs and DCs from GF and conventional pigs at different ages. These results further highlighted that the commensal microbiota of neonates play a critical role through TLR signaling in the development of systemic and mucosal immune systems.

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Genomic structure, promoter analysis and expression of the porcine (Sus scrofa) TLR4 gene

Cited by 32 publications

References 21 publications

Liver X Receptor Activation Potentiates the Lipopolysaccharide Response in Human Macrophages

Liver X Receptor Activation Potentiates the Lipopolysaccharide Response in Human Macrophages

A Comparative Review of Toll-Like Receptor 4 Expression and Functionality in Different Animal Species

Tissue-specific mRNA expression profiles of porcine Toll-like receptors at different ages in germ-free and conventional pigs

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