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1
Bergman, Ingrid-Maria, Amelie Johansson, Caroline Fossum, Leif Andersson, and Inger Edfors-Lilja. "Genetic analysis of porcine TLR genes." Veterinary Immunology and Immunopathology 128, no. 1-3 (March 2009): 218–19. http://dx.doi.org/10.1016/j.vetimm.2008.10.022.
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Liu, Long, Yu-Shan Wei, and Dun Wang. "Identification of Core Genes of Toll-like Receptor Pathway from Lymantria dispar and Induced Expression upon Immune Stimulant." Insects 12, no. 9 (September 14, 2021): 827. http://dx.doi.org/10.3390/insects12090827.
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The gypsy moth, Lymantria dispar, is a polyphagous forest pest worldwide. The baculovirus, Lymantria dispar multiple nucleopolyhedrovirus (LdMNPV) is a natural pathogen of L. dispar. The Toll-like receptors (TLR) pathway plays a crucial role in both innate and adaptive immunity in animals. However, The TLR pathway and its underlying immune mechanism against baculovirus in L. dispar have not been explored. In this study, eleven TLRs and five downstream TLR pathway components were identified and characterized from L. dispar. Structural analysis indicated that intracellular Toll/interleukin-1 receptor (TIR) domains of LdTLRs and LdMyD88 contained three conserved motifs, and the 3D structures of TIR domains of LdTLRs possessed similar patterns in components arrangement and spatial conformation. The TLR proteins of L. dispar were placed into five monophyletic groups based on the phylogenetic analysis. LdTLR1, 2, 5, 6, 7, 8 and all identified downstream TLR pathway factors were highly induced upon LdMNPV infection, indicating that the TLR pathway of L. dispar was activated and might play a role in the immune response to LdMNPV infection. Collectively, these results help elucidate the crucial role of the TLR pathway in the immune response of L. dispar against LdMNPV, and offer a foundation for further understanding of innate immunity of the pest.
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Pryimenko, Nataliia O., Tetiana M. Kotelevska, Tetiana I. Koval, Vadym A. Bodnar, Liudmyla M. Syzova, and Stanislav S. Rudenko. "EFFICACY OF SPECIFIC PREVENTION OF INFLUENZA IN INDIVIDUALS WITH POLYMORPHISMS ARG753GLN OF TLR-2, LEU412PHE OF TLR-3, ASP299GLY OF TLR-4 GENES." Wiadomości Lekarskie 73, no. 9 (2020): 1944–49. http://dx.doi.org/10.36740/wlek202009209.
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The aim: Is to study the efficacy of influenza vaccination for individuals with polymorphism Arg753Gln of TLR-2 gene, Leu412Phe of TLR-3 gene, and Asp299Gly of TLR-4 gene. Materials and methods: 66 people with mutant genotypes and normal distribution of alleles of TLR-2, TLR-3, TLR-4 genes, aged 18-63, were inoculated with anti-influenza vaccine. The genotyping of Arg753Gln polymorphic site of TLR-2, Asp299Gly of TLR-4, and Leu412Phe of TLR-3 gene was carried out by polymerase chain reaction with oligonucleotide primers usage. The immunological efficacy of vaccination was evaluated by seroconversion, seroprotection, and dynamics of mean geometric titers of antibodies. Results: It has been established that individuals with mutant genotypes Arg/Gln of TLR-2, Leu/Phe, Phe/Phe of TLR-3, Asp/Gly of TLR-4 genes have a vaccinal response to administering anti-influenza vaccine at the level of subjects with normal distribution of TLR alleles, as evidenced by the growth in dynamics of mean geometric titers of antibodies to vaccine strains, the level of seroprotection and seroconversion. Clinical and epidemiological efficacy of vaccination in this category of people is characterized by: reduction of ARI cases in the postvaccinal period by 2,0-3,0 times; prevention of pneumonia in all vaccinated subjects; decrease in the frequency of bronchitis by 2,5-3,8 times. Conclusions: Effectiveness of influenza vaccination in individuals with Arg573Gln polymorphism of TLR-2, Leu412Phe of TLR-3, Asp299Gly of TLR-4 genes by immune and clinical epidemiological parameters is determined at the level of vaccinated subjects with normal distribution of TLR-2, TLR-3, TLR-4 alleles. Specific influenza immunization of people with polymorphic modified genotypes of TLR-2, TLR-3, TLR-4 genes can prevent the development of pneumonia and reduce the incidence of bronchitis.
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Cui, Jian, Greta J. Frankham, Rebecca N. Johnson, Adam Polkinghorne, Peter Timms, Denis O’Meally, Yuanyuan Cheng, and Katherine Belov. "SNP Marker Discovery in Koala TLR Genes." PLOS ONE 10, no. 3 (March 23, 2015): e0121068. http://dx.doi.org/10.1371/journal.pone.0121068.
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Ramos Aguila, Luis Carlos, Hafiza Javaira Ashraf, Jessica Paola Sánchez Moreano, Komivi Senyo Akutse, Bamisope Steve Bamisile, Liuyang Lu, Xiaofang Li, Jingyi Lin, Qing Wu, and Liande Wang. "Genome-Wide Identification and Characterization of Toll-like Receptors (TLRs) in Diaphorina citri and Their Expression Patterns Induced by the Endophyte Beauveria bassiana." Journal of Fungi 8, no. 8 (August 22, 2022): 888. http://dx.doi.org/10.3390/jof8080888.
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Toll-like receptors (TLRs) are pathogen recognition receptors (PRRs), which play key roles in helping the host immune system fight pathogen invasions. Systematic information on TLRs at the genome-wide level and expression profiling in response to endophytic colonization is very important to understand their functions but is currently lacking in this field. Here, a total of two TLR genes were identified and characterized in Diaphorina citri. The TLR genes of D. citri were clustered into five families according to the phylogenetic analysis of different species’ TLRs. The domain organization analyses suggested that the TLRs were constituted of three important parts: a leucine-rich repeat (LRR) domain, a transmembrane region (TR) and a Toll/interleukin-1 receptor (TIR) domain. The mRNA expression levels of the two TLR genes (DcTOLL and DcTLR7) were highly regulated in both nymphs and adults of D. citri. These results elucidated the potentiated TLR gene expression in response to endophytically colonized plants. Furthermore, the 3D structures of the TIR domain were highly conserved during evolution. Collectively, these findings elucidate the crucial roles of TLRs in the immune response of D. citri to entomopathogens systematically established as endophytes, and provide fundamental knowledge for further understanding of the innate immunity of D. citri.
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Fajar, Jonny Karunia. "H1 antihistamines in allergic rhinitis: The molecular pathways of interleukin and toll - like receptor systems." Journal of Health Sciences 6, no. 1 (March 25, 2016): 1. http://dx.doi.org/10.17532/jhsci.2016.272.
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The complex interaction between inflammatory mediators in allergic rhinitis (AR) is determined by the role of genetic polymorphisms, including interleukin (IL) and toll-like receptor (TLR) genes. This study aimed to discuss the effects of H1-antihistamines on IL and TLR systems. Several ILs involved in AR pathogenesis are: IL-4 (rs2243250, rs1800925, rs1801275, rs2227284, rs2070874), IL-6 (rs1800795, rs1800797), IL-10 (rs1800871, rs1800872), IL-12R (rs438421), IL-13 (rs1800925, rs20541), IL-17 (rs3819024), IL-18 (rs360721, rs360718, rs360717, rs187238), IL-23R (rs7517847), and IL-27 (rs153109, rs17855750). In the IL system, histamines stimulate the IL production in Type 2 helper T (Th2) cells through protein kinase A (PKA), janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway, and the activation of H1-histamine receptor and histidine decarboxylase (HDC) genes. On contrary, antihistamines down-regulate the H1-histamine receptor gene expression through the transcription suppression of HDC and IL genes and suppress histamine basal signaling through the inverse agonistic activity. TLRs involved in AR pathogenesis are TLR2 (rs4696480, rs3804099, rs5743708), TLR4 (rs4986790), TLR6 (rs2381289), TLR7 (rs179008, rs5935438), TRL8 (rs2407992, rs5741883, rs17256081, rs4830805, rs3788935, rs178998), and TLR10 (rs11466651). In the TLR system, histamines trigger the TLR expression by stimulating interferon-γ (IFN-γ) to up-regulate mast cells and by stimulating receptor-interacting protein (RIP) to activate IκB kinase-β. Contrastingly, antihistamines suppress TIR-domain-containing adaptor protein inducing IFN-β (TRIF) and RIP protein and thus inhibit the expression of TLR. In addition, several studies indicated that H1-antihistamines inhibit the IL and TLR systems indirectly.
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Tantia, M. S., Bina Mishra, P. Banerjee, J. Joshi, S. Upasna, and R. K. Vijh. "Phylogenetic and sequence analysis of toll like receptor genes (TLR-2 and TLR-4) in buffaloes." Indian Journal of Animal Sciences 82, no. 8 (August 14, 2012): 875–78. http://dx.doi.org/10.56093/ijans.v82i8.23016.
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The toll like receptors play a significant role in innate immune response with TLR2 and TLR4 genes being associated with mastitis in cattle. The sequences of these genes were not known in buffaloes and in the present study we sequenced these 2 genes in buffaloes using 24 samples belonging to 6 diverse buffalo breeds of India. Primers were designed from the cattle data base and the buffalo genomic DNA was amplified. The gene sequences obtained after alignment were submitted to NCBI. The TLR2 gene was 3590 bases with 2 exons and coding for 784 amino acids. The TLR4 gene was 4256 nucleotide bases and consisted of 3 exons and coded for 841 amino acids. Eight SNPs were detected in TLR2 gene out of which 3 were non-synonymous. 25 SNPs were detected in TLR4 gene and out of which 10 were non-synonymous leading to change in amino acids. The 2 genes were found to be highly conserved across all mammalian species, and the phylogenetic relationship revealed the closeness of buffalo species with other ruminants, viz. cattle, sheep and goat compared to mono-gastric animals, viz. pigs and man.
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Sharbafi, Mohammad Hossein, Sara Assadiasl, Fatemeh Pour‐reza‐gholi, Saeed Barzegari, Peyman Mohammadi Torbati, Shiva Samavat, Mohammad Hossein Nicknam, and Aliakbar Amirzargar. "TLR‐2, TLR‐4 and MyD88 genes expression in renal transplant acute and chronic rejections." International Journal of Immunogenetics 46, no. 6 (July 9, 2019): 427–36. http://dx.doi.org/10.1111/iji.12446.
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Shaik-Dasthagirisaheb, Yazdani, Steve Shen, Caroline Genco, and Frank Gibson III. "Ageing and expression of TLR pathway associated genes in macrophages to Porphyromonas gingivalis challenge. (55.26)." Journal of Immunology 188, no. 1_Supplement (May 1, 2012): 55.26. http://dx.doi.org/10.4049/jimmunol.188.supp.55.26.
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Abstract Background: Periodontal disease is a chronic inflammatory disease that leads to progressive loss of soft and hard tissues supporting the teeth. Porphyromonas gingivalis (Pg) is a bacterium closely associated with periodontal disease. Toll-like receptors (TLR) and their intracellular signaling pathways play roles in host response to Pg. The focus of the current study was to define the expression profile of TLR pathway associated genes in macrophages (MØ) cultured with Pg, and to define changes in expression of these genes as a consequence of ageing. Methods: Bone marrow MØ from 2 months and1 year old wild type (WT), TLR2 knockout (KO), TLR4KO, MyD88KO and LPS2 mice were cultured with Pg. RNA was harvested from unchallenged and Pg challenged cells and expression of TLR pathway associated genes was measured by qPCR microarrays. Results: Pg challenge of WT MØ induced expression of a large set of TLR pathway associated genes. MØ gene expression data revealed 19, 48, 45 and 56 genes differentially regulated in TLR2KO, TLR4KO, MyD88KO and LPS2 mice respectively as compared with WT in response to Pg. We identified 19 genes that are commonly regulated in all four mutant genotypes. Age had little effect on the differential regulation of these genes by mutant MØ as compared with WT. Conclusions: Regulation of TLR pathway associated genes by MØ was highly responsive to Pg challenge. Pg challenge and mouse genotype had the strongest effects on gene expression in this model.
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Melnichuk, Nataliia, Vladimir Kashuba, Svitlana Rybalko, and Zenoviy Tkachuk. "Complexes of Oligoribonucleotides with d-Mannitol Modulate the Innate Immune Response to Influenza A Virus H1N1 (A/FM/1/47) In Vivo." Pharmaceuticals 11, no. 3 (July 22, 2018): 73. http://dx.doi.org/10.3390/ph11030073.
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Rapid replication of the influenza A virus and lung tissue damage caused by exaggerated pro-inflammatory host immune responses lead to numerous deaths. Therefore, novel therapeutic agents that have anti-influenza activities and attenuate excessive pro-inflammatory responses that are induced by an influenza virus infection are needed. Oligoribonucleotides-d-mannitol (ORNs-d-M) complexes possess both antiviral and anti-inflammatory activities. The current research was aimed at studying the ORNs-d-M effects on expression of innate immune genes in mice lungs during an influenza virus infection. Expression of genes was determined by RT-qPCR and Western blot assays. In the present studies, we found that the ORNs-d-M reduced the influenza-induced up-expression of Toll-like receptors (TLRs) (tlr3, tlr7, tlr8), nuclear factor NF-kB (nfkbia, nfnb1), cytokines (ifnε, ifnk, ifna2, ifnb1, ifnγ, il6, il1b, il12a, tnf), chemokines (ccl3, ccl4, сcl5, cxcl9, cxcl10, cxcl11), interferon-stimulated genes (ISGs) (oas1a, oas2, oas3, mx1), and pro-oxidation (nos2, xdh) genes. The ORNs-d-M inhibited the mRNA overexpression of tlr3, tlr7, and tlr8 induced by the influenza virus, which suggests that they impair the upregulation of NF-kB, cytokines, chemokines, ISGs, and pro-oxidation genes induced by the influenza virus by inhibiting activation of the TLR-3, TLR-7, and TLR-8 signaling pathways. By impairing activation of the TLR-3, TLR-7, and TLR-8 signaling pathways, the ORNs-d-M can modulate the innate immune response to an influenza virus infection.
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Airapetov, M. I., S. O. Eresko, P. D. Ignatova, D. A. Skabelkin, A. A. Mikhailova, D. A. Ganshina, A. A. Lebedev, E. R. Bychkov, and P. D. Shabanov. "The effect of rifampicin on expression of the toll-like receptor system genes in the forebrain cortex of rats prenatally exposed to alcohol." Biomeditsinskaya Khimiya 69, no. 4 (2023): 228–34. http://dx.doi.org/10.18097/pbmc20236904228.
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Ethanol causes long-term changes in the toll-like receptor (TLR) system, promoting activation of neuroinflammation pathways. Alcohol use during pregnancy causes neuroinflammatory processes in the fetus; this can lead to the development of symptoms of fetal alcohol spectrum disorder (FASD). Our study has shown that prenatal alcohol exposure (PAE) induced long-term changes in the TLR system genes (Tlr3, Tlr4, Ticam, Hmgb1, cytokine genes) in the forebrain cortex of rat pups. Administration of rifampicin (Rif), which can reduce the level of pro-inflammatory mediators in various pathological conditions of the nervous system, normalized the altered expression level of the studied TLR system genes. This suggests that Rif can prevent the development of persistent neuroinflammatory events in the forebrain cortex of rat pups caused by dysregulation in the TLR system.
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Brennan, Joseph J., Jonathan L. Messerschmidt, Leah M. Williams, Bryan J. Matthews, Marinaliz Reynoso, and Thomas D. Gilmore. "Sea anemone model has a single Toll-like receptor that can function in pathogen detection, NF-κB signal transduction, and development." Proceedings of the National Academy of Sciences 114, no. 47 (November 6, 2017): E10122—E10131. http://dx.doi.org/10.1073/pnas.1711530114.
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In organisms from insects to vertebrates, Toll-like receptors (TLRs) are primary pathogen detectors that activate downstream pathways, specifically those that direct expression of innate immune effector genes. TLRs also have roles in development in many species. The sea anemone Nematostella vectensis is a useful cnidarian model to study the origins of TLR signaling because its genome encodes a single TLR and homologs of many downstream signaling components, including the NF-κB pathway. We have characterized the single N. vectensis TLR (Nv-TLR) and demonstrated that it can activate canonical NF-κB signaling in human cells. Furthermore, we show that the intracellular Toll/IL-1 receptor (TIR) domain of Nv-TLR can interact with the human TLR adapter proteins MAL and MYD88. We demonstrate that the coral pathogen Vibrio coralliilyticus causes a rapidly lethal disease in N. vectensis and that heat-inactivated V. coralliilyticus and bacterial flagellin can activate a reconstituted Nv-TLR–to–NF-κB pathway in human cells. By immunostaining of anemones, we show that Nv-TLR is expressed in a subset of cnidocytes and that many of these Nv-TLR–expressing cells also express Nv-NF-κB. Additionally, the nematosome, which is a Nematostella-specific multicellular structure, expresses Nv-TLR and many innate immune pathway homologs and can engulf V. coralliilyticus. Morpholino knockdown indicates that Nv-TLR also has an essential role during early embryonic development. Our characterization of this primitive TLR and identification of a bacterial pathogen for N. vectensis reveal ancient TLR functions and provide a model for studying the molecular basis of cnidarian disease and immunity.
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Buxadé, Maria, Giulia Lunazzi, Jordi Minguillón, Salvador Iborra, Rosa Berga-Bolaños, Margarita del Val, José Aramburu, and Cristina López-Rodríguez. "Gene expression induced by Toll-like receptors in macrophages requires the transcription factor NFAT5." Journal of Experimental Medicine 209, no. 2 (February 6, 2012): 379–93. http://dx.doi.org/10.1084/jem.20111569.
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Toll-like receptors (TLRs) engage networks of transcriptional regulators to induce genes essential for antimicrobial immunity. We report that NFAT5, previously characterized as an osmostress responsive factor, regulates the expression of multiple TLR-induced genes in macrophages independently of osmotic stress. NFAT5 was essential for the induction of the key antimicrobial gene Nos2 (inducible nitric oxide synthase [iNOS]) in response to low and high doses of TLR agonists but is required for Tnf and Il6 mainly under mild stimulatory conditions, indicating that NFAT5 could regulate specific gene patterns depending on pathogen burden intensity. NFAT5 exhibited two modes of association with target genes, as it was constitutively bound to Tnf and other genes regardless of TLR stimulation, whereas its recruitment to Nos2 or Il6 required TLR activation. Further analysis revealed that TLR-induced recruitment of NFAT5 to Nos2 was dependent on inhibitor of κB kinase (IKK) β activity and de novo protein synthesis, and was sensitive to histone deacetylases. In vivo, NFAT5 was necessary for effective immunity against Leishmania major, a parasite whose clearance requires TLRs and iNOS expression in macrophages. These findings identify NFAT5 as a novel regulator of mammalian anti-pathogen responses.
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Kawagoe, Tatsukata, Shintaro Sato, Andreas Jung, Masahiro Yamamoto, Kosuke Matsui, Hiroki Kato, Satoshi Uematsu, Osamu Takeuchi, and Shizuo Akira. "Essential role of IRAK-4 protein and its kinase activity in Toll-like receptor–mediated immune responses but not in TCR signaling." Journal of Experimental Medicine 204, no. 5 (May 7, 2007): 1013–24. http://dx.doi.org/10.1084/jem.20061523.
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Interleukin-1 receptor–associated kinase 4 (IRAK-4) was reported to be essential for the Toll-like receptor (TLR)– and T cell receptor (TCR)–mediated signaling leading to the activation of nuclear factor κB (NF-κB). However, the importance of kinase activity of IRAK family members is unclear. In this study, we investigated the functional role of IRAK-4 activity in vivo by generating mice carrying a knockin mutation (KK213AA) that abrogates its kinase activity. IRAK-4KN/KN mice were highly resistant to TLR-induced shock response. The cytokine production in response to TLR ligands was severely impaired in IRAK-4KN/KN as well as IRAK-4−/− macrophages. The IRAK-4 activity was essential for the activation of signaling pathways leading to mitogen-activated protein kinases. TLR-induced IRAK-4/IRAK-1–dependent and –independent pathways were involved in early induction of NF-κB–regulated genes in response to TLR ligands such as tumor necrosis factor α and IκBζ. In contrast to a previous paper (Suzuki, N., S. Suzuki, D.G. Millar, M. Unno, H. Hara, T. Calzascia, S. Yamasaki, T. Yokosuka, N.J. Chen, A.R. Elford, et al. 2006. Science. 311:1927–1932), the TCR signaling was not impaired in IRAK-4−/− and IRAK-4KN/KN mice. Thus, the kinase activity of IRAK-4 is essential for the regulation of TLR-mediated innate immune responses.
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Sasaki, Reina, Tatsuo Kanda, Mariko Fujisawa, Naoki Matsumoto, Ryota Masuzaki, Masahiro Ogawa, Shunichi Matsuoka, Kazumichi Kuroda, and Mitsuhiko Moriyama. "Different Mechanisms of Action of Regorafenib and Lenvatinib on Toll-Like Receptor-Signaling Pathways in Human Hepatoma Cell Lines." International Journal of Molecular Sciences 21, no. 9 (May 9, 2020): 3349. http://dx.doi.org/10.3390/ijms21093349.
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Multiple kinase inhibitors are available for patients with advanced hepatocellular carcinoma (HCC). It is largely unknown whether regorafenib or lenvatinib modulates innate immunity including Toll-like receptor (TLR)-signaling pathways in HCC. We performed real-time RT-PCR to investigate 84 TLR-associated gene expression levels and compared these gene expression levels in each hepatoma cells treated with or without regorafenib or lenvatinib. In response to regorafenib, nine and 10 genes were upregulated in Huh7 and HepG2 cells, respectively, and only C-X-C motif chemokine ligand 10 was upregulated in both cell lines. A total of 14 and 12 genes were downregulated in Huh7 and HepG2 cells, respectively, and two genes (Fos proto-oncogene, AP-1 transcription factor subunit, and ubiquitin conjugating enzyme E2 N) were downregulated in both cell lines. In response to lenvatinib, four and 16 genes were upregulated in Huh7 and HepG2 cells, respectively, and two genes (interleukin 1 alpha and TLR4) were upregulated in both cells. Six and one genes were downregulated in Huh7 and HepG2, respectively, and no genes were downregulated in both cell lines. In summary, regorafenib and lenvatinib affect TLR signaling pathways in human hepatoma cell lines. Modulation of TLR signaling pathway may improve the treatment of HCC patients with refractory disease.
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Mukhtar, Maryam, Nadeem Sheikh, Andleeb Batool, Tayyaba Saleem, Muhammad Babar Khawar, Mavra Irfan, and Saira Kainat Suqaina. "TLR-8, TNF-α, and ESR-1α Gene Polymorphism Susceptibility in Onset of Arthritis." Genetics Research 2022 (September 20, 2022): 1–11. http://dx.doi.org/10.1155/2022/9208765.
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Arthritis is a genetic disorder characterized by bones and joint degradation assisted by severe pain and inflammation. It is evident by the studies that 0 candidate genes variations play vital role in its development and progression. Therefore, we investigated the genetic variation of TLR-8, TNF, and ESR-1α genes in the Pakistani population. A case-control study comprising 300 RA, 316 OA, and 412 control subjects was conducted. PCR-RFLP and direct sequencing methods were used for determining genetic variations. Analysis was performed by using PLINK and MEGA 6.0 software. Allelic and genetic frequencies of polymorphisms identified on rs3764879 (TLR-8), rs3764880 (TLR-8), rs5744080 (TLR-8), rs1800629 (TNF), rs2228480 (ESR-1α), and rs1451501590 (ESR-1α) were significantly varied among RA, OA, and controls. Novel functional mutations SCV000844945 and SCV000844946 on TLR-8 as well as a non-functional SCV000804801 and functional variation SCV000804802 on ESR-1α were also identified and reported for the first time in the studied population. Multiple site analyses indicated that polymorphisms on TLR-8 and ESR-1α genes were significant risk factors in disease onset to the next generation. In conclusion, TLR-08 and ESR-1α were significant in the onset of arthritis whereas the TNF was not found as a significant risk factor in the onset of RA and OA.
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Ma’at, Suprapto. "Toll-like Receptor (TLR) dan Imunitas Natura." INDONESIAN JOURNAL OF CLINICAL PATHOLOGY AND MEDICAL LABORATORY 15, no. 3 (March 16, 2018): 111. http://dx.doi.org/10.24293/ijcpml.v15i3.978.
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In all living species, the first line of defence against microbial aggressions is constituted by innate immunity. Toll-like receptors(TLRs) are a family of pattern recognition receptors that are activated by specific components of microbes and certain host molecules.They constitute the first line of defense against many pathogens and play a crucial role in the function of the innate immune system.Recognition of pathogen-associated molecular pattern (PAMP) by TLR, alone or heterodimerization with other TLR or non-TLR receptors,induces signals responsible for the activation of genes important for an effective host defense, especially proinflammatory cytokines, orinitiates signal transduction pathways, which trigger expression of genes. These gene products control innate immune responses andfurther instruct development of antigen-specific acquired immunity.
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Fitzner, Nicole, Sigrid Clauberg, Frank Essmann, Joerg Liebmann, and Victoria Kolb-Bachofen. "Human Skin Endothelial Cells Can Express All 10 TLR Genes and Respond to Respective Ligands." Clinical and Vaccine Immunology 15, no. 1 (October 31, 2007): 138–46. http://dx.doi.org/10.1128/cvi.00257-07.
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ABSTRACT Breakdown of the skin barrier requires the recognition of and rapid responses to invading pathogens. Since wounding usually also affects endothelial intactness, the expression of receptors of the Toll-like family involved in pathogen recognition in human skin vessel endothelia was examined. We found that human skin-derived microvascular endothelial cells can express all 10 Toll-like receptors (TLRs) currently known and will respond to respective ligands. Using immortalized skin-derived (HMEC-1) and primary dermal endothelial cells (HDMEC), we screened for TLR expression by real-time PCR. Endothelial cells express 7 (for HDMEC) and 8 (for HMEC-1) of the 10 known human TLRs under resting conditions but can express all 10 receptors in proinflammatory conditions. To provide evidence of TLR functionality, endothelial cells were challenged with TLR ligands, and after the TLR downstream signaling, MyD88 recruitment as well as early (interleukin-8 [IL-8] release) and late immune markers (inducible nitric oxide synthase mRNA expression) were monitored. Surprisingly, the responses observed were not uniform but were highly specific depending on the respective TLR ligand. For instance, lipopolysaccharides highly increased IL-8 release, but CpG DNA induced significant suppression. Additionally, TLR-specific responses were found to differ between resting and activated endothelial cells. These results show that human skin-derived endothelial cells can function as an important part of the innate immune response, can actively sense pathogen-associated molecular patterns, and can mount an increased or reduced inflammatory signal upon exposure to any of the currently known TLR ligands. Moreover, we also show here that proinflammatory conditions may affect TLR expression in a specific and nonuniform pattern.
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Wong-Baeza, Carlos, Alonso Tescucano, Horacio Astudillo, Albany Reséndiz, Carla Landa, Luis España, Jeanet Serafín-López, et al. "Nonbilayer Phospholipid Arrangements Are Toll-Like Receptor-2/6 and TLR-4 Agonists and Trigger Inflammation in a Mouse Model Resembling Human Lupus." Journal of Immunology Research 2015 (2015): 1–15. http://dx.doi.org/10.1155/2015/369462.
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Systemic lupus erythematosus is characterized by dysregulated activation of T and B cells and autoantibodies to nuclear antigens and, in some cases, lipid antigens. Liposomes with nonbilayer phospholipid arrangements induce a disease resembling human lupus in mice, including IgM and IgG antibodies against nonbilayer phospholipid arrangements. As the effect of these liposomes on the innate immune response is unknown and innate immune system activation is necessary for efficient antibody formation, we evaluated the effect of these liposomes on Toll-like receptor (TLR) signaling, cytokine production, proinflammatory gene expression, and T, NKT, dendritic, and B cells. Liposomes induce TLR-4- and, to a lesser extent, TLR-2/TLR-6-dependent signaling in TLR-expressing human embryonic kidney (HEK) cells and bone marrow-derived macrophages. Mice with the lupus-like disease had increased serum concentrations of proinflammatory cytokines, C3a and C5a; they also had more TLR-4-expressing splenocytes, a higher expression of genes associated with TRIF-dependent TLR-4-signaling and complement activation, and a lower expression of apoptosis-related genes, compared to healthy mice. The percentage of NKT and the percentage and activation of dendritic and B2 cells were also increased. Thus, TLR-4 and TLR-2/TLR-6 activation by nonbilayer phospholipid arrangements triggers an inflammatory response that could contribute to autoantibody production and the generation of a lupus-like disease in mice.
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Koval, M., and O. Sorokina. "The role of TLR-2 and TLR-4 gene polymorphisms in the development of sepsis in children with severe burns." Journal of Education, Health and Sport 12, no. 4 (April 20, 2022): 140–51. http://dx.doi.org/10.12775/jehs.2022.12.04.012.
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Recently, many studies are based on the study of innate immunity genes, namely the role of TLRs in the development of various diseases. Severe burn injury is characterized by the development of hyperimmune reactions, which further leads to the development of multiple organ complications and sepsis. The aim of our study was to identify the frequency and prognostic value of polymorphism of TLR-2 Arg753Gln and TLR-4 Thr399 Ile genes and their role in the development of sepsis and MOD in children with severe burns. Materials and methods: genetic analysis of TLR-2 Arg 753 Gln and TLR-4 Thr399 Ile gene polymorphisms was performed in children with severe and extremely severe burns (n = 22) who were treated in the anesthesiology department with intensive care beds. Results: as a result of the obtained data, the heterozygous genotype TLR-2 Arg 753 Gln was detected in 69.5% (n = 16), in 31.8% (n = 7) patients with burn injury polymorphism was not detected. In 13.6% (n = 3) cases, polymorphism was associated with sepsis and MOD. Sepsis and normal homozygous genotype were diagnosed in 4.5% (n = 1). Heterozygous genotype TLR-4 Thr399 Ile was observed in 18.2% (n = 4) patients, of which only 4.5% (n = 1) patients had polymorphism associated with sepsis and MOD. Analysis of the association of TLR 2 genotypes and markers of acute inflammation revealed statistically significant differences between the heterozygous TLR 2 Arg 753 Gln genotype and C-reactive protein (CRP) levels in the blood of patients on day 3 of burn disease. Conclusions: The study of the role of innate immune system genes is promising in predicting the development of sepsis and complications in severe burns and requires further careful study.
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Harberts, Erin, Rita Fishelevich, and Anthony Gaspari. "TLR agonist treatment elicits an increase in DNA repair machinery (117.19)." Journal of Immunology 188, no. 1_Supplement (May 1, 2012): 117.19. http://dx.doi.org/10.4049/jimmunol.188.supp.117.19.
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Abstract The toll-like receptor (TLR) pathway is stimulated by pathogen associated molecular patterns (PAMPs) and damage associated molecular patterns (DAMPs). Activation of this pathway leads to an inflammatory and immunomodulating response appropriate for the stimulus by which it was activated. Recently a body of literature has emerged indicating that TLR stimulation may not only result in an inflammatory response, but may also lead to an up-regulation of DNA repair genes and an increase in functional DNA repair after injury. These conclusions are drawn from studies conducted in the mouse animal model, however the human DNA repair response to TLR activation has yet to be investigated. Using an in vitro cell culture system, we find that human DNA repair genes are similarly up-regulated. Previously, only TLR 7 and TLR 9 agonists have been shown in mice to stimulate increased DNA repair; in this study we expand the panel of TLR agonists investigated and show that the induction of this phenomenon may not be unique to the previously studied TLR agonists. This functional increase in repair after injury may lead to a wide range of outcomes for the cells involved and warrants further study into the ever broadening role of TLR signaling in controlling cell fate.
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Matissek, Stephan Josef, Katja Koeppen, and Sherine F. Elsawa. "TLR-TRIF signaling induces GLI3 to modulate inflammation." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 152.5. http://dx.doi.org/10.4049/jimmunol.204.supp.152.5.
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Abstract Chronic inflammation is associated with several disorders and therefore the identification of novel regulators of inflammation is needed. We identified GLI3 as a novel component of the TLR-TRIF signaling. Stimulation of monocytes with LPS increased GLI3 expression in a hedgehog-independent mechanism. We stimulated cells with MPLA, (TLR4 ligand that signals through TRIF) and polyI:C (TLR3 ligand) and found that IRF3 directly binds to the GLI3 promoter and IRF3 increased GLI3 expression. We generated a conditional knockout (cko) mouse where GLI3 was deleted in myeloid cells using LysM-Cre mediated recombination. IFA-elicited macrophages from cko mice stimulated with LPS showed reduced IL-6, CCL2 and TNF-a secretion compared to macrophages from wild-type (wt) littermates. We also performed RNA sequencing of LPS treated or untreated macrophages from GLI3 cko or wt mice. Using a generalized linear model in edgeR, we identified 495 genes with significant interaction effects between genotype and LPS treatment. Ingenuity Pathway Analysis of the interaction genes revealed “Inflammatory Response” and “Immune Cell Trafficking” pathways as most significantly enriched. The 25 significant interaction genes on these pathways included 9 with a positive interaction (Ccl25, Cd226, Cgas, Hmgn5, Il12b, Lrrc8a, Rapgef3, Rnf122, and Tlr8) and 16 with a negative interaction (Acacb, Adipoq, Ccl1, Ccne1, Cx3cl1, Fry, Gstk1, Mertk, Nqo2, Slc6a4, Sort1, Timd4, Tnfrsf18/GITR, Tnfsf13/APRIL, Tnfsf13b/BAFF, and Trem2). Taken together, these results identify a novel role for GLI3 in mediating TLR-TRIF-induced inflammation and identify a novel set of inflammatory genes that are dependent on GLI3 in response to TLR-TRIF signaling.
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Kurt, Robert A., Chiquita Palha De Sousa, Christopher Blum, and Erica Sgroe. "Murine mammary carcinoma cells and CD11c+ dendritic cells elicit distinct responses to lipopolysaccharide and exhibit differential expression of genes required for TLR4 signaling (40.4)." Journal of Immunology 182, no. 1_Supplement (April 1, 2009): 40.4. http://dx.doi.org/10.4049/jimmunol.182.supp.40.4.
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Abstract Particular attention has been given to Toll-like receptors (TLR) on dendritic cells (DC) because of their ability to bridge innate and adaptive defenses. Since TLR are also expressed by epithelial cells, and because the majority of cancers are carcinomas, and thus of epithelial origin, we were interested in comparing responsiveness of a carcinoma and DC to a TLR agonist. For this purpose we used the mammary carcinoma 4T1 and CD11c+ DC. Both 4T1 and DC expressed genes encoding multiple TLR and secreted the proinflammatory chemokines CCL2 and CXCL1 in response to the TLR4 agonist lipopolysaccharide (LPS). However, DC, but not 4T1 secreted IL-1beta, TNF-alpha, and upregulated CD80 and CD86 expression following LPS treatment. Gene arrays were used to delineate potential reasons for the differential responsiveness of the cells to LPS. The arrays showed that genes encoding TLR4, CD14, myeloid differentiation primary response gene 88 (Myd88), and Toll-like receptor adaptor molecule 2 (TICAM-2) were expressed at greater levels by the DC; results which were verified by quantitative RT-PCR. These data demonstrate that 4T1 and CD11c+ DC are distinctly responsive to LPS, and that this may be a consequence of differential expression of genes encoding proteins important for TLR signaling.
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Noguchi, Taketoshi, Toshiyuki Sado, Katsuhiko Naruse, Hiroshi Shigetomi, Akira Onogi, Shoji Haruta, Ryuji Kawaguchi, et al. "Evidence for Activation of Toll-Like Receptor and Receptor for Advanced Glycation End Products in Preterm Birth." Mediators of Inflammation 2010 (2010): 1–10. http://dx.doi.org/10.1155/2010/490406.
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Objective. Individuals with inflammation have a myriad of pregnancy aberrations including increasing their preterm birth risk. Toll-like receptors (TLRs) and receptor for advanced glycation end products (RAGE) and their ligands were all found to play a key role in inflammation. In the present study, we reviewed TLR and RAGE expression, their ligands, and signaling in preterm birth.Research Design and Methods. A systematic search was performed in the electronic databases PubMed and ScienceDirect up to July 2010, combining the keywords “preterm birth,” “TLR”, “RAGE”, “danger signal”, “alarmin”, “genomewide,” “microarray,” and “proteomics” with specific expression profiles of genes and proteins.Results. This paper provides data on TLR and RAGE levels and critical downstream signaling events including NF-kappaB-dependent proinflammatory cytokine expression in preterm birth. About half of the genes and proteins specifically present in preterm birth have the properties of endogenous ligands “alarmin” for receptor activation. The interactions between the TLR-mediated acute inflammation and RAGE-mediated chronic inflammation have clear implications for preterm birth via the TLR and RAGE system, which may be acting collectively.Conclusions. TLR and RAGE expression and their ligands, signaling, and functional activation are increased in preterm birth and may contribute to the proinflammatory state.
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Farina, Giuseppina Alessandra, Antonella Farina, Mara Cirone, Michael York, Stefania Lenna, Cristina Padilla, Sarah Mclaughlin, Alberto Faggioni, Maria Trojanowska, and Robert Lafyatis. "Epstein-Barr virus infection induces aberrant TLR/MyD88 activation pathway and fibroblast-myofibroblast conversion in systemic sclerosis. (P6322)." Journal of Immunology 190, no. 1_Supplement (May 1, 2013): 182.13. http://dx.doi.org/10.4049/jimmunol.190.supp.182.13.
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Abstract Activated fibroblasts, mainly myofibroblasts are considered the principal mediators of fibrogenesis in systemic sclerosis (SSc), although the origin of persistent activation of fibroblasts and myofibroblasts is unclear. Activation of Interferon by Toll-like receptors in immune cells may play a role in the pathogenesis of inflammation in many autoimmune diseases, including SSc. We investigated whether fibroblasts persistently activated by innate immune and infectious stimuli might induce IFNs and TGFβ, two major markers of inflammation and fibrosis implicated in SSc pathogenesis. Since Epstein-Barr virus has been a leading candidate in triggering several autoimmune diseases, we developed methodology for infecting SSc fibroblasts with this virus. We found that EBV signals through the TLR/MyD88-pathway in infected-fibroblasts, activating a distinct innate immune response characterized by the expression of selected IFN- and TGFβ-inducible genes. Intriguingly, activation of the TLR/MyD88-pathway by CpGODN2006 or R837 ligand, significantly induced IFN-regulated genes, but no expression of TGFβ-regulated genes was detected in TLR/MyD88-stimulated fibroblasts. EBV-TLR/MyD88 aberrant activation induces the expression of selected IRFs, ISGs, TGFβ1 and several markers of fibroblast activation, such as smooth-muscle-actin and Endothelin-1, and all of these genes play a key role in determining the pro-fibrotic phenotype in SSc-fibroblasts.
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Wen, Jake J., Keyan Mobli, Geetha L. Radhakrishnan, and Ravi S. Radhakrishnan. "Regulation of Key Immune-Related Genes in the Heart Following Burn Injury." Journal of Personalized Medicine 12, no. 6 (June 20, 2022): 1007. http://dx.doi.org/10.3390/jpm12061007.
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Immune cascade is one of major factors leading to cardiac dysfunction after burn injury. TLRs are a class of pattern-recognition receptors (PRRs) that initiate the innate immune response by sensing conserved molecular patterns for early immune recognition of a pathogen. The Rat Toll-Like Receptor (TLR) Signaling Pathway RT² Profiler PCR Array profiles the expression of 84 genes central to TLR-mediated signal transduction and innate immunity, and is a validated tool for identifying differentially expressed genes (DEGs). We employed the PCR array to identify burn-induced cardiac TLR-signaling-related DEGs. A total of 38 up-regulated DEGs and 19 down-regulated DEGs were identified. Network analysis determined that all DEGS had 10 clusters, while up-regulated DEGs had 6 clusters and down-regulated DEGs had 5 clusters. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis showed that DEGs were involved in TLR signaling, the RIG-I-Like receptor signaling pathway, the IL-17 signaling pathway, and the NFkB signaling pathway. Function analysis indicated that DEGs were associated with Toll-like receptor 2 binding, Lipopeptide binding, Toll-like receptor binding, and NAD(P)+ nucleosidase activity. The validation of 18 up-regulated DEGs (≥10-fold change) and 6 down-regulated DEGs (≤5-fold change) demonstrated that the PCR array is a trusted method for identifying DEGs. The analysis of validated DEG-derived protein–protein interaction networks will guide our future investigations. In summary, this study not only identified the TLR-signaling-pathway-related DEGs after burn injury, but also confirmed that the burn-induced cardiac cytokine cascade plays an important role in burn-induced heart dysfunction. The results will provide the novel therapeutic targets to protect the heart after burn injury.
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Blumhagen, Rachel Z., Brenna R. Hedin, Kenneth C. Malcolm, Ellen L. Burnham, Marc Moss, Edward Abraham, Tristan J. Huie, Jerry A. Nick, Tasha E. Fingerlin, and Scott Alper. "Alternative pre-mRNA splicing of Toll-like receptor signaling components in peripheral blood mononuclear cells from patients with ARDS." American Journal of Physiology-Lung Cellular and Molecular Physiology 313, no. 5 (November 1, 2017): L930—L939. http://dx.doi.org/10.1152/ajplung.00247.2017.
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A key physiological feature of acute respiratory distress syndrome (ARDS) is inflammation. Toll-like receptor (TLR) signaling is required to combat the infection that underlies many ARDS cases but also contributes to pathological inflammation. Several TLR signaling pathway genes encoding positive effectors of inflammation also produce alternatively spliced mRNAs encoding negative regulators of inflammation. An imbalance between these isoforms could contribute to pathological inflammation and disease severity. To determine whether splicing in TLR pathways is altered in patients with ARDS, we monitored alternative splicing of MyD88 and IRAK1, two genes that function in multiple TLR pathways. The MyD88 and IRAK1 genes produce long proinflammatory mRNAs (MyD88L and IRAK1) and shorter anti-inflammatory mRNAs (MyD88S and IRAK1c). We quantified mRNA encoding inflammatory cytokines and MyD88 and IRAK1 isoforms in peripheral blood mononuclear cells (PBMCs) from 104 patients with ARDS and 30 healthy control subjects. We found that MyD88 pre-mRNA splicing is altered in patients with ARDS in a proinflammatory direction. We also observed altered MyD88 isoform levels in a second critically ill patient cohort, suggesting that these changes may not be unique to ARDS. Early in ARDS, PBMC IRAK1c levels were associated with patient survival. Despite the similarities in MyD88 and IRAK1 alternative splicing observed in previous in vitro studies, there were differences in how MyD88 and IRAK1 alternative splicing was altered in patients with ARDS. We conclude that pre-mRNA splicing of TLR signaling genes is altered in patients with ARDS, and further investigation of altered splicing may lead to novel prognostic and therapeutic approaches.
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Ekwemalor, Kingsley, and Mulumebet Worku. "PSX-41 Effect of Polyinosinic-polycytidylic acid on gene expression in goat blood." Journal of Animal Science 97, Supplement_3 (December 2019): 449. http://dx.doi.org/10.1093/jas/skz258.884.
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Abstract The objective of this study was to investigate the effect of Polyinosinic-polycytidylic [poly(I:C)] acid on gene activation in goat blood. Polyinosinic-polycytidylic acid is a synthetic dsRNA analogue that binds to Toll-like receptor (TLR) 3. Synthetic TLR agonists are promising immune modulators. Blood samples were collected from the jugular vein of BoerXSpanish goats (n = 3) into tubes containing an anticoagulant. Whole blood was treated with the 12.5 µg/ml of poly I:C or 200µl of PBS which served as control. Cells were incubated at 37°C with 5% CO2 and 85% humidity for 30 minutes. Total RNA was isolated from the pellet using Trizol and then converted to cDNA using RETROscript kit (Qiagen). The expression of 84 genes in the human TLR signaling pathway RT2 PCR Array was evaluated using real-time PCR. Fold change in gene expression was calculated using the 2−ΔΔCt method. The housekeeping gene GAPDH, ACTB, HPRT1, TBP, and YWHAZ was used to normalize the data. Fold change was set at a cutoff of 2. Following treatment with poly I:C, 24 genes were up-regulated, 15 genes were down-regulated. The gene MAPK8 was induced by poly I:C treatment. Only 74 genes were expressed in the control. Thirty-nine genes were expressed in both the control group and poly I:C treatment group. Treatment with poly I:C also down-regulated some of the genes tested. Our results show that treatment poly I:C modulated the expression of genes in the TLR signaling pathway and provides insights into how goats respond to viral pathogens for the design of adjuvants to enhance the immune response.
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Foldi, Julia, Xiaoyu Hu, Allen Y. Chung, and Lionel B. Ivashkiv. "Regulation of Notch ligands by the TLR and IFN-γ pathways in macrophages (135.63)." Journal of Immunology 182, no. 1_Supplement (April 1, 2009): 135.63. http://dx.doi.org/10.4049/jimmunol.182.supp.135.63.
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Abstract Jagged and Delta proteins are transmembrane ligands for the Notch family of receptors. The role for Notch and its ligands in innate immunity remains largely unknown. Our lab recently identified a subset of Toll like receptor (TLR)-inducible genes that were activated synergistically, by TLR-ligands and the Notch pathway. Some of these genes were also regulated by interferon (IFN)-γ, a potent macrophage activator. To further elucidate the role of the Notch pathway in innate immunity, we would like to know how Notch ligands are regulated in macrophages. We found that Jagged-1 and Delta-like (Dll)-1 were induced by TLR ligation and were regulated by IFN-γ in CD14+ primary human monocytes and in mouse bone-marrow-derived macrophages. TLR-induced upregulation of Jagged-1 was independent of de novo protein synthesis and the mitogen activated protein kinase (MAPK) pathway, while the nuclear factor (NF)-κB and Notch pathways played a role in this process. IFN-γ pre-treatment of cells super-induced TLR-stimulated Jagged-1, while it inhibited Dll-1 upregulation. In conclusion, Jagged and Delta proteins are synergistically regulated by the TLR, Notch and IFN-γ pathways in macrophages. This work is supported by the Cancer Research Institute (CRI) Predoctoral Fellowship.
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Al-Fatlawi, Manar Mohammed Hadi, Mahdi Hussain Al-Ammar, and Yasir Lafta Hassoun Al-Manssori. "Study of gene expression of Cytokine Genes (TLR-4, NOD-2) in patients with Otitis Media in Al-Najaf Governorate, Iraq." BIO Web of Conferences 84 (2024): 03019. http://dx.doi.org/10.1051/bioconf/20248403019.
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The study aimed to evaluate the gene expression of genes (TLR-4,NOD-2) in patients of Otitis media and healthy persons. This finding included 50 samples that collected from healthy subject and 100 samples from a patients suffering from otitis media who attended Al-Sadr Medical City (ENT Department) in Al-Najaf Governorate during the period from February 2022 to June 2022. The samples had an average age ranging from 5 to 70 years. The gene expression of these genes among those suffering from Otitis media and healthy individuals have been investigated in this case-control research. Using a PCR technology. polymerase chain reactions were carried out to amplify each sample for the patient and control groups. The results of the molecular study (gene expression) showed a high significant increase in the level of gene expression in patients for the two genes NOD-2, TLR-4 genes (14.78 ± 2.369, 16.42 ± 3.158), respectively, with a significant difference at P≤0.05. TLR-4, NOD-2 as used as a molecular diagnosis Otitis Media patients.
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Aluri, Jahnavi, Megan A. Cooper, and Laura G. Schuettpelz. "Toll-Like Receptor Signaling in the Establishment and Function of the Immune System." Cells 10, no. 6 (June 2, 2021): 1374. http://dx.doi.org/10.3390/cells10061374.
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Toll-like receptors (TLRs) are pattern recognition receptors that play a central role in the development and function of the immune system. TLR signaling promotes the earliest emergence of hematopoietic cells during development, and thereafter influences the fate and function of both primitive and effector immune cell types. Aberrant TLR signaling is associated with hematopoietic and immune system dysfunction, and both loss- and gain-of- function variants in TLR signaling-associated genes have been linked to specific infection susceptibilities and immune defects. Herein, we will review the role of TLR signaling in immune system development and the growing number of heritable defects in TLR signaling that lead to inborn errors of immunity.
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Gao, Yunan, Yan Sun, Adife Gulhan Ercan-Sencicek, Justin S. King, Brynn N. Akerberg, Qing Ma, Maria I. Kontaridis, William T. Pu, and Zhiqiang Lin. "YAP/TEAD1 Complex Is a Default Repressor of Cardiac Toll-Like Receptor Genes." International Journal of Molecular Sciences 22, no. 13 (June 22, 2021): 6649. http://dx.doi.org/10.3390/ijms22136649.
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Toll-like receptors (TLRs) are a family of pattern recognition receptors (PRRs) that modulate innate immune responses and play essential roles in the pathogenesis of heart diseases. Although important, the molecular mechanisms controlling cardiac TLR genes expression have not been clearly addressed. This study examined the expression pattern of Tlr1, Tlr2, Tlr3, Tlr4, Tlr5, Tlr6, Tlr7, Tlr8, and Tlr9 in normal and disease-stressed mouse hearts. Our results demonstrated that the expression levels of cardiac Tlr3, Tlr7, Tlr8, and Tlr9 increased with age between neonatal and adult developmental stages, whereas the expression of Tlr5 decreased with age. Furthermore, pathological stress increased the expression levels of Tlr2, Tlr4, Tlr5, Tlr7, Tlr8, and Tlr9. Hippo-YAP signaling is essential for heart development and homeostasis maintenance, and YAP/TEAD1 complex is the terminal effector of this pathway. Here we found that TEAD1 directly bound genomic regions adjacent to Tlr1, Tlr2, Tlr3, Tlr4, Tlr5, Tlr6, Tlr7, and Tlr9. In vitro, luciferase reporter data suggest that YAP/TEAD1 repression of Tlr4 depends on a conserved TEAD1 binding motif near Tlr4 transcription start site. In vivo, cardiomyocyte-specific YAP depletion increased the expression of most examined TLR genes, activated the synthesis of pro-inflammatory cytokines, and predisposed the heart to lipopolysaccharide stress. In conclusion, our data indicate that the expression of cardiac TLR genes is associated with age and activated by pathological stress and suggest that YAP/TEAD1 complex is a default repressor of cardiac TLR genes.
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Lepelletier, Yves, Raphaël Zollinger, Cristina Ghirelli, Françoise Raynaud, Réda Hadj-Slimane, Antonio Cappuccio, Olivier Hermine, Yong-Jun Liu, and Vassili Soumelis. "Toll-like receptor control of glucocorticoid-induced apoptosis in human plasmacytoid predendritic cells (pDCs)." Blood 116, no. 18 (November 4, 2010): 3389–97. http://dx.doi.org/10.1182/blood-2010-05-282913.
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Abstract Microbial infection triggers the endogenous production of immunosuppressive glucocorticoid (GC) hormones and simultaneously activates innate immunity through toll-like receptors (TLRs). How innate immune cells integrate these 2 opposing signals in dictating immunity or tolerance to infection is not known. In this study, we show that human plasmacytoid predendritic cells (pDCs) were highly sensitive to GC-induced apoptosis. Strikingly, they were protected by microbial stimulation through TLR-7 and TLR-9, but not by microbial-independent stimuli, such as interleukin-3, granulocyte macrophage colony-stimulating factor, or CD40-ligand. This protection was dependent on TLR-induced autocrine tumor necrosis factor-α and interferon-α, which collectively increased the expression ratio between antiapoptotic genes (Bcl-2, Bcl-xL, BIRC3, CFLAR) versus proapoptotic genes (Caspase-8, BID, BAD, BAX). In particular, virus-induced Bcl-2 up-regulation was dependent on autocrine interferon-α. Using small interfering RNA technology, we demonstrated that Bcl-2 and CFLAR/c-flip were essential for TLR-induced protection of pDCs from GC-induced caspase-8–mediated apoptosis. Our results demonstrate a novel property of the TLR pathway in regulating the interface between GC and innate immunity and reveal a previously undescribed mechanism of GC resistance.
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Lani, Rafidah, Boon-Teong Teoh, Sing-Sin Sam, Sazaly AbuBakar, and Pouya Hassandarvish. "Fisetin Modulates Toll-like Receptor-Mediated Innate Antiviral Response in Chikungunya Virus-Infected Hepatocellular Carcinoma Huh7 Cells." Immuno 2, no. 4 (November 25, 2022): 703–19. http://dx.doi.org/10.3390/immuno2040043.
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In the chronic phase of chikungunya virus (CHIKV) infection, excessive inflammation manifests as incapacitating joint pain and prolonged arthritis. Arthritis resulted from a large influx of infiltrating immune cells driven by pro-inflammatory cytokines and chemokines originating from the toll-like receptor (TLR)-mediated innate antiviral response. This study investigated fisetin’s ability to modulate TLR-mediated antiviral responses against CHIKV in Huh7 cells. The CHIKV inhibitory potential of fisetin was assessed by plaque-forming unit assay, virus yield reduction assay, and bright-field microscopy (cytopathic effect, immunofluorescence). Fisetin’s modulatory potential on TLR-mediated antiviral response was evaluated by immunofluorescence assay (expression of TLR proteins), qRT-PCR (mRNA level of antiviral genes), human cytokine array, and the immunoblotting of key transcription factors. The present study showed fisetin induced the expression of the antiviral genes at an early time-point by promoting the phosphorylation of IRF3 and IRF7. Fisetin reduced excessive inflammatory cytokine responses in CHIKV-infected Huh7 cells by impeding the over-phosphorylation of NF-κB. Fisetin also reduced CHIKV-induced cytopathic effects in CHIKV-infected Huh7 cells. Altogether, our study suggests that fisetin modulates TLR-mediated antiviral responses by affecting the CHIKV-induced inflammatory responses.
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Moradi, Maryam, Alireza Tabibzadeh, Davod Javanmard, Saied Ghorbani, Farah Bokharaei-Salim, Hosein Keivani, Mohammad Khazeni, and Seyed Hamid Reza Monavari. "Assessment of Key Elements in the Innate Immunity System Among Patients with HIV, HCV, and Coinfections of HIV/HCV." Current HIV Research 18, no. 3 (June 12, 2020): 194–200. http://dx.doi.org/10.2174/1570162x18999200325162533.
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Background: Coinfection of Hepatitis C virus (HCV) with human immunodeficiency virus (HIV) has a higher risk of mortality than HCV or HIV monoinfection. HCV and HIV infections are specified by systemic inflammation, but the inflammation process in HCV/HIV coinfection is much complicated and is not well characterized. Objective: The aim of this study was to analyze the expression of TLR-3, TLR-7, IL-10, IFN-1 (IFN-α, IFN-β), and TNF-α in HIV, HCV and HIV/HCV co-infected patients. Methods: Forty-five patients including HIV group (n=15), HCV group (n=15), HIV/HCV coinfection group (n=15) and healthy control group (n=15) participated. Peripheral blood mononuclear cells (PBMCs) were obtained. PBMC-RNA, HCV and HIV RNA were extracted from all subjects and cDNA was synthesized. The viral load analyzed by reverse transcription-quantitative PCR (RT-qPCR), and the expression levels of IFN-α, IFN-β, TLR-3, TLR-7, TNF, and IL-10 mRNA were quantified in PBMCs. Results: The levels of IFN-I, IL-10, and TNF-α were overexpressed in all patients’ groups (P<0.05), TLR-7 was upregulated in all groups, but this upregulation was not statistically significant (p>0.05). TLR-3 showed a decrease in all patient groups (P<0.05). The statistical analysis demonstrated that TLR-3 has a negative correlation with HIV load, whereas other genes positively correlated with HIV load. In addition, TLR-3, TNF-α, and IFN-I were negatively correlated with HCV load, whereas TLR-7 and IL-10 s were positively correlated with HCV load. Conclusion: Our results showed a significant relationship between the expression level of innate immunity genes and inflammation in HCV, HIV, and HIV/HCV coinfected patients.
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Plykanchuk, O. V., O. M. Muzychuk, M. A. Tkhorovskiy, O. P. Nezgoda, and T. I. Klymenko. "The significance of tlr genes, in particular TLR-2 and TLR-4, and their polymorphisms in susceptibility and resistance to the development and clinical course of tuberculosis." Reports of Vinnytsia National Medical University 27, no. 2 (May 29, 2023): 341–45. http://dx.doi.org/10.31393/reports-vnmedical-2023-27(2)-28.
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Annotation. The tuberculosis pandemic is a global problem of modern medicine, and thousands of scientists from all over the world are working towards finding a solution. Taking into account the fact that there are national and international programs to fight tuberculosis, nosology remains the second infectious cause of death in the world after COVID-19. Indeed, official WHO statistics indicate that 1.6 million people died from this serious infectious disease in 2021 alone. Resistance, susceptibility, and the course of the pathology largely depend not only on environmental factors and morphofunctional features of the pathogen but also on the patient's genotype, which prompted us to analyze the influence of TLR genes and their polymorphisms on the aforementioned characteristics. In accordance with the set goal, we processed the currently known information about TLR family genes, as well as their polymorphisms, using the main databases. Toll-like receptors (TLRs) are involved in the recognition of molecular patterns associated with Mycobacterium tuberculosis, which subsequently initiates the host's immune response. Thus, any failure in the cascade of the above-mentioned pathway will manifest itself in changes in the course of tuberculosis, as well as in resistance and susceptibility to it. Many data indicate a predisposition to nosology in the presence of TLR gene polymorphisms, and a significant number of researchers mention the severe course of the disease in patients with mutant genotypes. The understanding of pathophysiological mechanisms at the level of receptors and signaling pathways as a result of the influence of genetic mutations will enable us to fight the disease more thoroughly. The results of our review are aimed at improving the tactics of managing patients with tuberculosis, timely detection of nosology, and the development of modern methods of prevention.
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Rodríguez, Alianet, Janet Velázquez, Luis González, Tania Rodríguez-Ramos, Brian Dixon, Fidel Herrera Miyares, Antonio Morales, Osmany González, Mario Pablo Estrada, and Yamila Carpio. "PACAP modulates the transcription of TLR-1/TLR-5/MyD88 pathway genes and boosts antimicrobial defenses in Clarias gariepinus." Fish & Shellfish Immunology 115 (August 2021): 150–59. http://dx.doi.org/10.1016/j.fsi.2021.06.009.
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Zheng, Pan, Xue-Yang Li, Xiao-Yu Yang, Huan Wang, Ling Ding, Cong He, Jian-Hua Wan, et al. "Comparative transcriptomic analysis reveals the molecular changes of acute pancreatitis in experimental models." World Journal of Gastroenterology 30, no. 14 (April 14, 2024): 2038–58. http://dx.doi.org/10.3748/wjg.v30.i14.2038.
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BACKGROUND Acute pancreatitis (AP) encompasses a spectrum of pancreatic inflammatory conditions, ranging from mild inflammation to severe pancreatic necrosis and multisystem organ failure. Given the challenges associated with obtaining human pancreatic samples, research on AP predominantly relies on animal models. In this study, we aimed to elucidate the fundamental molecular mechanisms underlying AP using various AP models. AIM To investigate the shared molecular changes underlying the development of AP across varying severity levels. METHODS AP was induced in animal models through treatment with caerulein alone or in combination with lipopolysaccharide (LPS). Additionally, using Ptf1α to drive the specific expression of the hM3 promoter in pancreatic acinar cells transgenic C57BL/6J- hM3/Ptf1α(cre) mice were administered Clozapine N-oxide to induce AP. Subsequently, we conducted RNA sequencing of pancreatic tissues and validated the expression of significantly different genes using the Gene Expression Omnibus (GEO) database. RESULTS Caerulein-induced AP showed severe inflammation and edema, which were exacerbated when combined with LPS and accompanied by partial pancreatic tissue necrosis. Compared with the control group, RNA sequencing analysis revealed 880 significantly differentially expressed genes in the caerulein model and 885 in the caerulein combined with the LPS model. Kyoto Encyclopedia of Genes and Genomes enrichment analysis and Gene Set Enrichment Analysis indicated substantial enrichment of the TLR and NOD -like receptor signaling pathway, TLR signaling pathway, and NF-κB signaling pathway, alongside elevated levels of apoptosis-related pathways, such as apoptosis, P53 pathway, and phagosome pathway. The significantly elevated genes in the TLR and NOD -like receptor signaling pathways, as well as in the apoptosis pathway, were validated through quantitative real-time PCR experiments in animal models. Validation from the GEO database revealed that only MYD88 concurred in both mouse pancreatic tissue and human AP peripheral blood, while TLR1 , TLR7 , RIPK3 , and OAS2 genes exhibited marked elevation in human AP. The genes TUBA1A and GADD45A played significant roles in apoptosis within human AP. The transgenic mouse model hM3/Ptf1α(cre) successfully validated significant differential genes in the TLR and NOD -like receptor signaling pathways as well as the apoptosis pathway, indicating that these pathways represent shared pathological processes in AP across different models. CONCLUSION The TLR and NOD receptor signaling pathways play crucial roles in the inflammatory progression of AP, notably the MYD88 gene. Apoptosis holds a central position in the necrotic processes of AP, with TUBA1A and GADD45A genes exhibiting prominence in human AP.
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Georgel, Philippe, Cécile Macquin, and Seiamak Bahram. "The Heterogeneous Allelic Repertoire of Human Toll-Like Receptor (TLR) Genes." PLoS ONE 4, no. 11 (November 17, 2009): e7803. http://dx.doi.org/10.1371/journal.pone.0007803.
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Ruan, Wenke, Yanhua Wu, and Shijun J. Zheng. "Different genetic patterns in avian Toll-like receptor (TLR)5 genes." Molecular Biology Reports 39, no. 4 (June 30, 2011): 3419–26. http://dx.doi.org/10.1007/s11033-011-1113-7.
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Samaké, Kalifa, and Karel Novák. "Haplotype Disequilibrium in the TLR Genes of Czech Red Pied Cattle." Diversity 15, no. 7 (June 27, 2023): 811. http://dx.doi.org/10.3390/d15070811.
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Hybrid resequencing of the antibacterial innate immune genes coding for toll-like receptors, namely TLR1, TLR2, TLR4, TLR5, and TLR6, using HiSeq and PacBio technologies of pooled population samples of Czech Simmental (Czech Red) cattle allowed us to determine haplotypes formed by the polymorphisms present. Directly determined haplotypes within the range of the large proximal amplicon in TLR2 formed two clusters in the network tree graph. The distribution of the statistically reconstructed haplotypes based on individual genotyping of the present SNPs was consistent. Similarly, the statistically reconstructed haplotypes in TLR5 and TLR6 formed two clusters. The trend of bimodal distribution was also observed in TLR4, while the limited diversity of TLR1 did not allow for any conclusion. The observed bimodal distribution is consistent with earlier reports for cattle populations worldwide. The stability of this phenomenon cannot be ascribed to historical origin but rather to a long-term effect of balancing selection. The equilibrium might be based on two different essential functions performed by the TLR genes or their products. The formation of two kinds of heterodimers by the TLR2 product, namely, TLR2/TLR1 and TLR2/TLR6 with different ligand specificities, is considered to be a particular case. On the other hand, the better expression of the bimodal groups in the 5′-proximal SNPs supports the localization of the selection targets in the upstream regulatory regions or the functional interactions in the proximal part of the transcripts.
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Shabaldin, A. V., A. V. Sinitskaya, and S. A. Shmulevich. "Role of cytokine and Toll-like receptor genes in pathogenesis of inborn heart disease." Medical Immunology (Russia) 24, no. 3 (July 13, 2022): 605–16. http://dx.doi.org/10.15789/1563-0625-roc-2488.
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Sporadic congenital heart disease (CHD) may result from immune disorders in the mother – embryo system and/or constitutional disorders in regulatory systems, including those associated with TLR receptors, cytokines and their receptors. The aim of our study was to investigate associations between cytokine and TLR genes and sporadic congenital heart disease in children. In the main group, 188 children with sporadic (without family history) congenital heart defects were examined. Separate groups of CHD were identified: septal CHD – 98 children; valvular heart disease – 17 children; Fallot tetralogy – 15 children; aorta coarctation – 10 children; fetal drains – 32 children; single ventricle affection – 9 children, and anomalous drainage of v. pulmonalis was diagnosed in 7 children. The control group included 103 age- and sex-matched healthy children. We have determined gene polymorphisms of five genes encoding cytokines and their receptors (IL6 rs1800796, IL6 rs2069827, IL6R rs2228145, IL6R rs2229238, IL8 rs4073, IL10 rs1800871, IL10 rs1800896, IL10 rs1800872, TNF rs1800629, TNF rs361525, TNF rs1799964), four genes Toll-like receptors (TLR: TLR1 rs5743611, TLR1 rs5743551, TLR2 rs5743708, TLR2 rs3804099, TLR4 rs4986791, TLR4 rs4986790, TLR6 rs3775073, TLR6 rs5743810). The dbSNP, SNPinfo, SNPnexus databases were used to select and design test systems. Stepwise logistic regression was the main method of statistical analysis. Clinical diagnosis of congenital heart defects is associated with immune regulatory genes. In particular, the missense mutation TLR6 rs5743810, which was a predictor of congenital valvular heart disease, is of particular importance. Development of congenital heart valve defects and aortic coarctation is associated with intergenic interactions of TLR2 rs5743708 with TLR6 rs5743810, and TLR2 rs5743708 with TLR6 rs3775073, respectively. For congenital heart valve defects, such polymorphic regions are as follows: IL6 rs2069827, IL6R rs2229238, and IL8 rs4073, for aortic coarctation – IL6R rs2228145, IL8 rs4073. Development of septal congenital heart defects is associated with general contribution of polymorphic variants of the TLR genes and cytokines to this pathology. A missense mutation of the TLR4 rs4986790 gene and a TNF rs1799964 mutation leading to increased synthesis of the TNFα molecule, may have a combined effect on this process. In general, contribution of TLR and cytokine genes interactions to the CHD development seems to be not significant.
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Vlasova, D. D., A. A. Sadova, N. S. Germanov, V. S. Galina, V. A. Shmarov, O. V. Kutko, M. P. Rykova, et al. "THE IMPACT OF ARTIFICIAL GRAVITY MODELLED IN SHORT-ARM CENTRIFUGE ON THE EXPRESSION OF TLR-ASSOCIATED GENES OF INNATE IMMUNITY." Aerospace and Environmental Medicine 57, no. 2 (2023): 20–26. http://dx.doi.org/10.21687/0233-528x-2023-57-2-20-26.
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Here, we report the changes in the expression of TLR-associated genes, genes of NF-kB, AP-1, and TLR4 pathways, genes coding for apoptotic proteins, cytokines, and chemokines, after rotation on the short-arm centrifuge. The study involved 10 almost healthy male volunteers aged 25-40. CD14+ monocytes were isolated from the testers’ blood before and after the exposure to the artificial gravity. The cells were incubated with TLR1-9 ligands for 24 hours to assess the monocytes’ reserve potential. The gene expression was evaluated by real-time PCR. In sum, no negative effect of rotation on the short-arm centrifuge on the functioning of TLR-associated branch of innate immunity was detected.
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Е.С., Ершова,, Вейко, Н.Н., Салимова, Н.А., Каменева, Л.В., Долгих, О.А., and Костюк, С.В. "The effect of cfDNA on the expression of TLR receptors in human mesenchymal stem cells." Nauchno-prakticheskii zhurnal «Medicinskaia genetika, no. 11 (November 30, 2021): 25–35. http://dx.doi.org/10.25557/2073-7998.2021.11.25-35.
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Введение. Опосредованная толл-подобными рецепторами (TLR) активация врожденного иммунного ответа варьирует в зависимости от типа клеток. TLR могут узнавать не только экзогенныe патогенные молекулы (PAMP - pathogen-associated molecular patterns), но и молекулы эндогенной природы, появляющиеся при повреждении тканей, асептическом воспалении и дегенерации - DAMP. При определенных обстоятельствах эта реакция может быть неконтролируемой, что приводит к развитию тяжелого системного воспаления и сепсиса. TLR9 - единственный из TLR, который способен обнаруживать патогенные CpG-ДНК в эндолизосомных структурах. В составе внеклеточной ДНК (вкДНК) при патологии, при беременности и при действии повреждающих факторов накапливаются ГЦ-богатые фрагменты рибосомной ДНК (рДНК), являющиеся лигандами TLR9. Цель исследования: исследовать влияние разных по составу фрагментов вкДНК на экспрессию TLR9 и других TLR человека в клеточных культурах in vitro. Методы. Исследование проводилось на гистологически различающихся культурах с разным пролиферативным потенциалом: мезенхимные стволовые клетки (N=13), HUVEC (N=7) и клетки аденокарциномы молочной железы человека MCF7. Исследование экспрессии клетками поверхностных белков проводили методом проточной цитометрии. Для моделирования воздействия вкДНК на разные типы клеток были приготовлены модельные формы ДНК: геномная ДНК (гДНК) гидролизованная нуклеазой, окисленные формы гДНК и модельный ГЦ-обогащенный фрагмент ДНК - CpG-богатый фрагмент транскрибируемой области рДНК. Уровень экспрессии генов TLR 1-10 оценивали методом ПЦР в реальном времени. Результаты. Установлено повышение экспрессии генов внутриклеточных эндоплазматических рецепторов TLR3, TLR7 и TLR8 в ответ на воздействие как ГЦ-богатых, так и окисленных фрагментов вкДНК в разных типах клеток. Кроме того, в присутствии вкДНК возрастает экспрессия генов рецепторов клеточной поверхности TLR6 и, в меньшей степени, TLR1 и TLR5. При действии окисленных фрагментов возрастает экспрессия гена TLR4. Однако, повышение экспрессии генов семейства TLR возникает вторично после активации TLR9. Блокирование TLR9 ингибирует проведение сигнала и через остальные TLR. Заключение. Наблюдаемое при воздействии вкДНК увеличение экспрессии рецепторов семейства TLR, помимо TLR9, может быть связано с вовлечением сети рецепторов TLR в регуляцию проведения сигнала через TLR9, как через взаимодействия между рецепторами TLR, так через другие сигнальные пути, связанные с распознаванием вкДНК ДНК-сенсорами. Background. TLR-mediated activation of the innate immune response varies with cell type. TLRs can recognize not only exogenous pathogenic molecules (PAMP - pathogen-associated molecular patterns), but also endogenous molecules that appear during tissue damage, aseptic inflammation, and degeneration - DAMP. Under certain circumstances, this reaction may be uncontrollable, which leads to the development of severe systemic inflammation and sepsis. TLR9 is the only TLR that is capable of detecting pathogenic CpG DNA in endolysosomal structures. GC-rich rDNA fragments, which are TLR9 ligands, are accumulated in eDNA during pathology, pregnancy, or under the action of damaging factors. Aim: to investigate the influence of cfDNA fragments of different composition on the expression of TLR9 and on the expression of other human TLRs in in vitro cultures. Methods. The study was carried out on histologically different cultures with different proliferative potentials: mesenchymal stem cells (N = 13), HUVEC (N = 7), and MCF7 human breast adenocarcinoma cells. The expression of surface proteins by cells was studied by flow cytometry. To simulate the effect of eDNA on different types of cells, there were prepared model forms of DNA: genomic DNA (hydrolyzed by nuclease), oxidized forms of gDNA, and a model GC-enriched DNA fragment - CpG - a rich fragment of the transcribed region of rDNA. The expression level of TLR 1-10 genes was assessed by real-time PCR. Results. We noticed an increase in the expression of intracellular endoplasmic receptors TLR3, TLR7 and TLR8 genes in response to the action of both GC-rich and oxidized cfDNA fragments in different types of cells. In addition, the presence of cfDNA increases the expression of cell surface receptors TLR6 genes, and, to a lesser extent, TLR1 and TLR5. Under the action of oxidized fragments, the expression of the TLR4 gene increases. However, an increase in the expression of TLR family genes occurs secondarily after TLR9 activation. Blocking TLR9 inhibits signal transduction through other TLRs. Conclusions. Binding of An increase in the expression of receptors of the TLR family, except for TLR9, observed upon exposure to cfDNA, may be associated with the involvement of the TLR network in the regulation of signal transduction through TLR9, both through interactions between TLR receptors and through other signaling pathways associated with cfDNA recognition by DNA sensors.
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Kwissa, Marcin, Helder I. Nakaya, Herold Oluoch, and Bali Pulendran. "Distinct TLR adjuvants differentially stimulate systemic and local innate immune responses in nonhuman primates." Blood 119, no. 9 (March 1, 2012): 2044–55. http://dx.doi.org/10.1182/blood-2011-10-388579.
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Abstract TLR ligands (TLR-Ls) represent novel vaccine adjuvants, but their immunologic effects in humans remain poorly defined in vivo. In the present study, we analyzed the innate responses stimulated by different TLR-Ls in rhesus macaques. MPL (TLR4-L), R-848 (TLR7/8-L), or cytosine-phosphate-guanine oligodeoxynucleotide (TLR9-L) induced a rapid and robust expansion of blood neutrophils, with a concomitant reduction in PBMCs. Furthermore, all TLR-Ls induced rapid (3-8 hours) expansion of CD14+ monocytes, but only TLR7/8-L and TLR9-L mobilized the CD14+CD16+ and CD14dimCD16++ monocytes, and only TLR7/8-L and TLR9-L induced activation of myeloid dendritic cells (mDCs) and plasmacytoid DCs (pDCs), production of IP-10 and type-I IFN, and expression of type-I IFN–related and chemokine genes in the blood. In the draining lymph nodes (LNs), consistent with the effects in blood, all TLR-Ls induced expansion of CD14+ monocytes, but only TLR7/8-L and TLR9-L expanded the activated CD14+CD16+ cells. TLR4-L and TLR9-L differentially induced the expansion of mDCs and pDCs (1-3 days), but did not activate DCs. In contrast, TLR7/8-L did not induce DC expansion, but did activate mDCs. Finally, both TLR9-L and TLR7/8-L induced the expression of genes related to chemokines and type-I IFNs in LNs. Thus different TLR-Ls mediate distinct signatures of early innate responses both locally and systemically.
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Morenikeji, Olanrewaju, Jessica L. Metelski, and Bolaji Thomas. "Significant upregulation of signaling and pro-inflammatory markers indicate adaptation for tolerance in bovine trypanosomosis." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 92.7. http://dx.doi.org/10.4049/jimmunol.204.supp.92.7.
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Abstract The initial immune response on exposure to trypanosomosis is a significant factor mitigating disease tolerance or susceptibility in cattle. CD14 is a signaling receptor involved in the activation of the TLR signaling pathway, contributing to the production of cytokines, including tumor necrosis factor-α (TNF-α). We had shown that CD14 expression in trypanotolerant cattle is an adaptation footprint, not found in susceptible animals. To further our analysis in delineating the role of TLR-4 and TNF-α genes in disease tolerance or susceptibility, we examined whole transcriptome and interactome of the two genes by elucidating their expression profiles in bovine tissues (liver, lungs, heart and kidney). Our analyses demonstrate a significant (p< 0.05) upregulation of TLR-4 and TNF-α in trypanotolerant cattle but not others. The upregulation of these genes in tolerant animals reflects a complete activation of the innate immune pathway, thereby hampering disease establishment, which is absent in the susceptible animals. This is contrary to reports in human studies, where the expression of these genes lead to disease chronicity, rather than tolerance. This indicates an evolutionary differentiation between cattle and human during speciation. Furthermore, we catalogued microRNA expression between disease groups via network analysis and identified 13 candidate microRNAs targeting CD14, TLR-4 and TNF-α, amongst others, which GO analysis reveal are involved in gene silencing, cellular protein modification process, etc. We conclude that the upregulation of these markers and the significant co-regulatory interactome is indicative of adaptation footprint in tolerant animal, helpful for bovine immune response against trypanosomiasis.
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Xu, Jun, Robert Chain, Ana Gamero, and Stefania Gallucci. "STAT2 is required for TLR-induced cross-presentation (APP3P.109)." Journal of Immunology 192, no. 1_Supplement (May 1, 2014): 111.10. http://dx.doi.org/10.4049/jimmunol.192.supp.111.10.
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Abstract Type I Interferons (IFNs) are one of the principal mediators in cross-presentation of exogenous antigens to prime CD8+ T cells. Toll-like receptor (TLR) stimulation enhances cross-presentation in dendritic cells (DCs), however, the molecular mediators involved in TLR-induced cross-presentation remain to be elucidated. Since STAT2 is a critical signaling component in the canonical signaling pathway downstream of type I IFN receptor, we hypothesized that TLR-induced cross-presentation may require STAT2. We generated an in vitro model of murine conventional DCs, the bone marrow derived DCs (BMDCs) from WT and STAT2KO mice, and found that STAT2 deficiency did not affect GMCSF-dependent DC development in vitro. Yet upon TLR stimulation, we found STAT2 deficiency impaired the type I IFN response as postulated, including reduction in costimulatory molecules (MHC Class I and CD86), and in the up-regulation of IFN-stimulated genes. Furthermore, STAT2KO DCs were impaired in their expression of signal 3 cytokines, such as IL-12, upon TLR stimuli. To complement our findings, we performed in vitro cross-presentation assays using OT-I TCR transgenic (Tg) T cells, and found that both proliferation and IFN-γ production of CD8+ Tg T cells were reduced when primed with LPS- or CpG-induced STAT2KO BMDCs cross-presenting OVA. Hence, our current data demonstrate that STAT2/type I IFNs axis is essential for TLR4 and 9-induced cross-presentation.
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Tolba, Khaled A., William Bowers, Yaohong Tan, Sandrine Daubeuf, Howard J. Federoff, and Joseph D. Rosenblatt. "HSV ICP0 Inhibits TLR-Mediated NF-κB Response to TLR Signaling." Blood 108, no. 11 (November 16, 2006): 5487. http://dx.doi.org/10.1182/blood.v108.11.5487.5487.
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Abstract HSV infection activates a robust innate response through engagement of multiple pattern recognition receptors (PRR) including both TLR (TLR2 and TLR9) as well as non-TLR. Signaling events downstream of these receptors activate NF-κB and IRF3 responsive genes and initiate an innate inflammatory response aimed at controlling viral replication and spread. In this work, we studied immune suppressive activity of a replication-defective HSV virus and identified the immediate early protein ICP0 as a negative regulator of both NF-κB and IRF3 signaling. ICP0 possesses an ubiquitin E3 ligase function through its NH2 RING domain, as well as de-ubiquitinating activity through its association with the cellular de-ubiquitinating enzyme USP7 (HAUSP). We show that these two domains of ICP0 function independently to suppress IRF3 and NF-κB signaling, respectively and, in the process, effectively shut down host innate immunity to HSV infection. Although ICP0 inhibition of IRF3 has been reported, inhibition of TLR-mediated NF-κB response has not been previously described. We show that ICP0 globally inhibits NF-κB response to all TLR receptors as well as IL-1R. ICP0 exerts this activity by associating with USP7 and altering its cellular localization from a nuclear to cytoplasmic protein. In the cytosol, USP7 associates with and de-ubiquitinates TRAF6 and IKK-γ (NEMO), two signaling components of the TLR-mediated NF-κB pathway that are poly-ubiquitinated upon TLR activation. ICP-0 expression vectors harboring point mutations/deletions that target the RING domain E3 ligase function or compromise ICP-0 ability to bind USP7 would selectively inhibit its ability to interfere with either IRF3 or NF-kB signaling, respectively. In support of this, knockdown of endogenous USP7 by RNAi severely impaired ICP0-mediated inhibition of NF-κB response while leaving its capacity to inhibit IRF3 intact. In contrast, over-expression of USP-7 was sufficient to inhibit TLR-mediated NF-κB response. Ability of ICP-0 to inhibit both IRF3 and NF-κB signaling pathways, the former through its E3 ligase function and the latter through its association with USP-7, affords HSV comprehensive protection from host immunity during repeated cycles of lytic infection and reactivation from latency. The work also identifies a rare example of how two seemingly contradictory biologic functions resident within ICP0, namely ubiquitin E3 ligase activity at the NH2 terminus RING domain and de-ubiquitinating activity through association with USP-7, could cooperate to inhibit multiple signaling pathways necessary for efficient silencing of innate immunity. Finally, the work also identifies a previously unknown function for USP7 in regulating innate signaling beyond its known function as a regulator of p53.
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Björkbacka, Harry, Katherine A. Fitzgerald, François Huet, Xiaoman Li, James A. Gregory, Melinda A. Lee, Christine M. Ordija, Nicole E. Dowley, Douglas T. Golenbock, and Mason W. Freeman. "The induction of macrophage gene expression by LPS predominantly utilizes Myd88-independent signaling cascades." Physiological Genomics 19, no. 3 (November 17, 2004): 319–30. http://dx.doi.org/10.1152/physiolgenomics.00128.2004.
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Myeloid differentiation protein-88 (MyD88) is a signal adaptor protein required for cytokine production following engagement of Toll-like receptors (TLRs) by their cognate ligands. Activation of both TLR-3 and TLR-4, however, can engage signaling events independent of MyD88 expression. The relative importance of these MyD88-dependent and -independent signaling pathways in the macrophage response to lipopolysaccharide (LPS) is unknown. Here we define these events using microarray expression profiling of LPS-stimulated macrophages taken from MyD88-null and wild-type mice. Of the 1,055 genes found to be LPS responsive, only 21.5% were dependent on MyD88 expression, with MyD88-independent genes constituting 74.7% of the genetic response. This MyD88-independent gene expression was predominantly transcriptionally regulated, as it was unaffected by cycloheximide blockade of new protein synthesis. A previously undescribed group of LPS-regulated genes (3.8%), whose induction or repression was significantly greater in the absence of MyD88, was also identified by these studies. The regulation of these genes suggested that MyD88 could serve as a molecular brake, constraining gene activity in a subset of LPS-responsive genes. The findings generated with LPS stimulation were recapitulated by exposure of macrophages to live Escherichia coli. These expression-profiling studies redefine the current dogma of TLR-4 signaling and establish that MyD88, although essential for some of the best-characterized macrophage responses to LPS, is not required for the regulation of the majority of genes engaged by macrophage exposure to endotoxin or live bacteria.
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Kurt, Robert A., Thalia Newman, and Chun Wai Liew. "Predicting the therapeutic efficacy of TLR stimulated macrophages for cancer treatment." Journal of Immunology 210, no. 1_Supplement (May 1, 2023): 142.08. http://dx.doi.org/10.4049/jimmunol.210.supp.142.08.
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Abstract Macrophages play a variety of roles in immunity including both pro- and anti-inflammatory functions, which can be controlled by toll-like receptor (TLR) stimulation. Previously, we generated a computational model of interconnected TLR signaling cascades and validated the model using experimental data from the THP-1 monocyte cell line. This project aimed to adapt the computational model to provide insights into the activation of bone marrow-derived macrophages (BMDM) to enable the accurate prediction of BMDM therapeutic efficacy following TLR stimulation. Initially, we quantitated expression of genes encoding TLR signaling proteins in BMDM and THP-1 cells and found distinct differences between the cell types. For instance, IRAK2 was expressed in BMDM at a level over 150 times the expression level in THP-1 cells, while other genes, such as TLR4, were expressed at relatively similar levels. Next, these data were used to adapt the computational model to BMDM. In order to determine whether the model predicted the optimal way to activate the BMDM, the cells were treated with lipopolysaccharide and flagellin and IL-1b production was quantified by ELISA. The data revealed that the model did not predict the optimal way to achieve pro-inflammatory cytokine expression in the BMDM. We are currently altering the model to improve its ability to predict pro-inflammatory cytokine expression following TLR stimulation. In addition, studies are underway exploring the therapeutic efficacy of the TLR-stimulated BMDM using a murine mammary carcinoma model. The ultimate goal of this project is to produce a computational model capable of predicting how BMDM respond to TLR stimulation and to use the model to predict the anti-tumor efficacy of the BMDM.