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<abstract_text><p>Immune cells of the myeloid and lymphoid lineages express Toll-like receptors (TLRs) to recognize pathogenic components or cellular debris and activate the immune system through the secretion of cytokines. Cytoki...
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<abstract_text><p>Immune cells of the myeloid and lymphoid lineages express Toll-like receptors (TLRs) to recognize pathogenic components or cellular debris and activate the immune system through the secretion of cytokines. Cytokines are signaling molecules that are structurally and functionally distinct from one another, although their secretion profiles and signaling cascades often overlap. This situation gives rise to pleiotropic cell-to-cell communication pathways essential for protection from infections as well as cancers. Nonetheless, deregulated signaling can have detrimental effects on the host, in the form of inflammatory or autoimmune diseases. Because cytokines are associated with numerous autoimmune and cancerous conditions, therapeutic strategies to modulate these molecules or their biological responses have been immensely beneficial over the years. There are still challenges in the regulation of cytokine function in patients, even in those who take approved biological therapeutics. In this review, our purpose is to discuss the differential expression patterns of TLR-regulated cytokines and their cell type specificity that is associated with cancers and immune-system-related diseases. In addition, we highlight key structural features and molecular recognition of cytokines by receptors; these data have facilitated the development and approval of several biologics for the treatment of autoimmune diseases and cancers.</p></abstract_text>
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摘要 :
Immune cells of the myeloid and lymphoid lineages express Toll-like receptors (TLRs) to recognize pathogenic components or cellular debris and activate the immune system through the secretion of cytokines. Cytokines are signaling ...
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Immune cells of the myeloid and lymphoid lineages express Toll-like receptors (TLRs) to recognize pathogenic components or cellular debris and activate the immune system through the secretion of cytokines. Cytokines are signaling molecules that are structurally and functionally distinct from one another, although their secretion profiles and signaling cascades often overlap. This situation gives rise to pleiotropic cell-to-cell communication pathways essential for protection from infections as well as cancers. Nonetheless, deregulated signaling can have detrimental effects on the host, in the form of inflammatory or autoimmune diseases. Because cytokines are associated with numerous autoimmune and cancerous conditions, therapeutic strategies to modulate these molecules or their biological responses have been immensely beneficial over the years. There are still challenges in the regulation of cytokine function in patients, even in those who take approved biological therapeutics. In this review, our purpose is to discuss the differential expression patterns of TLR-regulated cytokines and their cell type specificity that is associated with cancers and immune-system-related diseases. In addition, we highlight key structural features and molecular recognition of cytokines by receptors; these data have facilitated the development and approval of several biologics for the treatment of autoimmune diseases and cancers.
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Toll-like receptors (TLRs) are the most upstream pattern recognition receptors in the cell, which detect pathogen associated molecular patterns and initiate signal transduction, culminating in the transcription of pro-inflammatory...
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Toll-like receptors (TLRs) are the most upstream pattern recognition receptors in the cell, which detect pathogen associated molecular patterns and initiate signal transduction, culminating in the transcription of pro-inflammatory cytokines and antiviral interferon. Interleukin-1 receptor-associated kinase 4 (IRAK4) is a key mediator in TLR (except for TLR3) and interleukin-1 receptor signaling pathways. The loss of kinase function of IRAK4 is associated with increased susceptibility to various pathogens, while its over-activation causes autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, and cancer. The therapeutic importance of this master kinase has been advocated by a number of recent preclinical studies, where potent inhibitors have been administered to improve various TLR-mediated pathologies. Increasing studies of X-ray crystallographic structures with bound inhibitors have improved our knowledge on the molecular recognition of ligands by IRAK4, which will be crucial for the development of new inhibitors with improved potencies. In this review, we briefly discuss the structural aspect of ligand recognition by IRAK4 and highlight its therapeutic importance in the context of TLR-associated unmet medical needs.
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Nucleotide binding and oligomerization domain 2 (NOD2), a member of intracellular NOD-like receptors (NLRs) family, recognizes the bacterial peptidoglycan, muramyl dipeptide (MDP) and initiates host immune response. The precise li...
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Nucleotide binding and oligomerization domain 2 (NOD2), a member of intracellular NOD-like receptors (NLRs) family, recognizes the bacterial peptidoglycan, muramyl dipeptide (MDP) and initiates host immune response. The precise ligand recognition mechanism of NOD2 has remained elusive, although studies have suggested leucine rich repeat (LRR) region of NOD2 as the possible binding site of MDP. In this study, we identified multiple transcripts of NOD2 gene in buffalo (buNOD2) and at least five LRR variants (buNOD2-LRRW (wild type), buNOD2-LRRVI-V4) were found to be expressed in buffalo peripheral blood mononuclear cells. The newly identified buNOD2 transcripts were shorter in lengths as a result of exon-skipping and frame-shift mutations. Among the variants, buNOD2-LRRW, V1, and V3 were expressed more frequently in the animals studied. A comparative receptor-ligand interaction study through modeling of variants, docking, and molecular dynamics simulation revealed that the binding affinity of buNOD2-LRRW towards MDP was greater than that of the shorter variants. The absence of a LRR segment in the buNOD2 variants had probably affected their affinity toward MDP. Notwithstanding a high homology among the variants, the amino acid residues that interact with MDP were located on different LRR motifs. The binding free energy calculation revealed that the amino acids Arg850(LRR4) and Glu932(LRR7) of buNOD2-LRRW, Lys810(LRR3) of buNOD2-LRRV1, and Lys830(LRR3) of buNOD2-LRRV3 largely contributed towards MDP recognition. The knowledge of MDP recognition and binding modes on buNOD2 variants could be useful to understand the regulation of NOD-mediated immune response as well as to develop next generation anti-inflammatory compounds. (C) 2016 Elsevier Inc. All rights reserved.
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Introduction: Pattern recognition receptors (PRRs) of the innate immune system mediate and control the activation and progression of adaptive immunity. Toll-like receptors (TLRs) are the most notable of the PRRs: they play crucial...
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Introduction: Pattern recognition receptors (PRRs) of the innate immune system mediate and control the activation and progression of adaptive immunity. Toll-like receptors (TLRs) are the most notable of the PRRs: they play crucial roles in protecting the host body against invading pathogens or endogenously released hazardous molecules. Sustained TLR signaling even after the clearance of pathogens or failure to distinguish between 'self' and 'non-self' molecules can cause inflammatory disorders, autoimmune diseases, and cancer.
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The copy number variation (CNV) is the number of copies of a particular gene in the genotype of an individual. Recent evidences show that the CNVs can vary in frequency and occurrence between breeds. These variations reportedly al...
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The copy number variation (CNV) is the number of copies of a particular gene in the genotype of an individual. Recent evidences show that the CNVs can vary in frequency and occurrence between breeds. These variations reportedly allowed different breeds to adapt to different environments. As copy number variations follow Mendelian pattern of inheritance, identification and distribution of these variants between populations can be used to infer the evolutionary history of the species. In this study, we have examined the absolute copy number of four Heat shock factor genes viz. HSF-1, 2, 4, and 5 in two different breeds of buffalo species using real-time PCR. Here, we report that the absolute copy number of HSF2 varies between the two breeds. In contrast no significant difference was observed in the copy number for HSF-1, 4, and 5 between the two breeds. Our results provide evidence for the presence of breed specific differences in HSF2 genomic copy number. This seems to be the first step in delineating the genetic factors underlying environmental adaptation between the two breeds. Nevertheless, a more detailed study is needed to characterize the functional consequence of this variation.
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A novel noninvasive genomic DNA isolation protocol from fecal tissue, by the proteinase K digestion and guanidine hydrochloride extraction method, was assessed for the genotyping of cattle and buffalo. The epithelial tissues prese...
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A novel noninvasive genomic DNA isolation protocol from fecal tissue, by the proteinase K digestion and guanidine hydrochloride extraction method, was assessed for the genotyping of cattle and buffalo. The epithelial tissues present on the surface of the feces were used as source for isolation of genomic DNA. The DNA isolated from fecal tissue was found to be similar as those obtained from other body tissues such as skin, brain, liver, kidney, and muscle. The quality of DNA was checked by agarose gel electrophoresis and polymerase chain reaction (PCR). We successfully amplified a 320 bp MHC class II DRB gene and a 125 bp mt-DNA D-loop region from isolated genomic DNA of cattle. Thus, the DNA isolated using this method was suitable for common molecular biology methods, such as restriction enzyme digestion and genotyping of dairy animals through PCR.
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