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An enzyme that senses foreign and mislocated DNA in the cell cytoplasm acts as an alarm that triggers host defense responses. [Also see Research Article by Sun et al. and Report by Wu et al. ]
No abstract is provided for this article.
Toll-like receptor (TLR) signal transduction is mediated by an adaptor protein termed MyD88. In the case of TLR2 and TLR4, another adaptor related to MyD88 called Mal also participates in signalling. Two recent papers have added a third adaptor to the family, called Toll–interleukin-1 receptor (TIR) domain-containing adaptor inducing interferon-β (IFN-β) (TRIF) or TIR-containing adaptor molecule-1 (TICAM-1), which is particularly important for IFN regulatory factor-3 (IRF-3) activation by antiviral TLR3. Two additional adaptors are present in humans, termed Trif-related adaptor molecule (TRAM) and sterile α and HEAT–Armadillo motifs (SARM). It is probable that differential use of adaptors will help explain the distinct pathways activated by TLRs during host defence.
No abstract is provided for this article.
Review on the link between miR-107 dyregulation and TLR4 inflammation in type 2 diabetes. miRNAs are small noncoding RNAs that act as regulators of gene expression. Dysregulation of miRNAs has been shown to contribute to multiple disease processes. It has become apparent that miRNAs play a key role in the innate immune response, whereby a large number of miRNAs have been demonstrated to be regulated by TLRs, key initiators of the innate immune response to infection. Recently, the LPS receptor, TLR4, has been shown to down-regulate miR-107 in macrophages. In addition, miR-107 has been demonstrated to be dysregulated in murine and rodent models of obesity and insulin resistance, respectively, with miR-107 contributing to both conditions. With obesity and inflammation being so intrinsically associated, the link between the miR-107 expression levels, inflammation, and insulin resistance may be of particular importance in metabolic diseases. The decrease in miR-107 in response to TLR4 may be an attempt to limit insulin resistance, a feature of obesity-related inflammation. If this process is impaired, disease, such as T2D, might persist. This review aims to discuss a possible link between the molecular phenomena of obesity and inflammation and the role that miR-107 may contribute to these processes.
No abstract is provided for this article.
The pathogenesis of type 2 diabetes, Alzheimer's disease and amyotrophic lateral sclerosis continues to be debated. Recently, the inflammasome protein complex has been shown to be a key regulator of IL-1β, a cytokine implicated in each of these diseases. In all three cases, it is now apparent that unique protein aggregates caused by inappropriate oligomerization or misfolding are sensed by the inflammasome, providing a unifying mechanism for this IL-1β production. What evolved as an innate defense against infection-related particles, therefore, now seems to be a driving force for inflammation in these diseases. This review discusses the basic research behind these findings and the potential for new therapeutic interventions this affords.
Atherosclerosis is the cause of morbiditiy for 70% of patients with type 2 diabetes. In both of these diseases, a protein complex known as the inflammasome is stimulated to activate interleukin-1β (IL-1β) and IL-18, which are pathogenic inflammatory cytokines. Triggers for the inflammasome are obesity-related factors, such as cholesterol crystals in atherosclerosis, or hyperglycemia, ceramides, and islet amyloid polypeptide in type 2 diabetes. Therapeutics that target IL-1β in clinical trials for type 2 diabetes might also decrease the incidence of atherosclerosis.
Conference Article| February 01 1996 Mechanism of NFκB activation by interleukin-1 and tumour necrosis factor in endothelial cells Andrew Bowie; Andrew Bowie 1Biochemistry Department, Trinity College Dublin, Ireland Search for other works by this author on: This Site PubMed Google Scholar Paul N. Moynagh; Paul N. Moynagh ∗Pharmacology Department, University College Dublin, Ireland. Search for other works by this author on: This Site PubMed Google Scholar Luke A.J. O'neill Luke A.J. O'neill 1Biochemistry Department, Trinity College Dublin, Ireland Search for other works by this author on: This Site PubMed Google Scholar Biochem Soc Trans (1996) 24 (1): 2S. https://doi.org/10.1042/bst024002s Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Facebook Twitter LinkedIn MailTo Cite Icon Cite Get Permissions Citation Andrew Bowie, Paul N. Moynagh, Luke A.J. O'neill; Mechanism of NFκB activation by interleukin-1 and tumour necrosis factor in endothelial cells. Biochem Soc Trans 1 February 1996; 24 (1): 2S. doi: https://doi.org/10.1042/bst024002s Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search Search Dropdown Menu toolbar search search input Search input auto suggest filter your search All ContentAll JournalsBiochemical Society Transactions Search Advanced Search Keywords: EC, endothelial cell, IL1, interleukin-1, NAC, N-acetyl cysteine, PDTC, pyrrolidine dithiocarbamate, PMA, phorbol 12-myristate 13-acetate, ROS, reactive oxygen species, TNF, tumour necrosis factor This content is only available as a PDF. © 1996 Biochemical Society1996 Article PDF first page preview Close Modal You do not currently have access to this content.
Transcription factors provide the link between early membrane-proximal signalling events and changes in gene expression. NF-kB is one of the best-characterized transcription factors. It is expressed ubiquitously and regulates the expression of many genes, most of which encode proteins that play an important and often determining role in the processes of immunity and inflammation. Apart from its role in these events, evidence has begun to accumulate that NF-kB is involved in brain function, particularly following injury and in neurodegenerative conditions such as Alzheimer's disease. NF-kB might also be important for viral replication in the CNS. An involvement of NF-kB in neuronal development is suggested from studies that demonstrate its activation in neurones in certain regions of the brain during neurogenesis. Brain-specific activators of NF-kB include glutamate (via both AMPA/KA and NMDA receptors) and neurotrophins, pointing to an involvement in synaptic plasticity. NF-kB can therefore be considered as one of the most important transcription factors characterized in brain to date and it might be as crucial for neuronal and glial cell function as it is for immune cells.
A key aspect of innate immunity is the recognition of pathogen-derived factors by macrophages. Toll-like receptors (TLRs) play a key role in this process, with TLR-4 recognizing lipopolysaccharide (LPS) from Gram-negative bacteria, and TLR-2 recognizing products such as peptidoglycan and lipopeptide from Gram-positive bacteria and zymosan from yeast. Eight other TLRs have been found, with TLR-9 recently being shown to recognize bacterially-derived CpG DNA. The function of the other TLRs is not known.
No abstract is provided for this article.
Accessory molecules play a crucial role in the development of the T cell response to antigenic challenge. We have examined the role of CD28 in modulating the 'naive' neonatal T cell response to anti-CD2-mediated activation. To compare the role of CD28, neonatal and adult T cells were stimulated with a pair of mitogenic anti-CD2 antibodies in the presence or absence of anti-CD28 MoAb. With anti-CD2 alone, neonatal T cells proliferated slightly but produced no detectable IL-2, whereas adult T cells proliferated vigorously, with significant IL-2 production. Costimulation with anti-CD28 MoAb greatly enhanced the proliferative response of neonatal T cells to levels equivalent to those of adult T cells, whereas adult T cells showed only slight increases. Although IL-2 secretion was increased in the presence of anti-CD28 MoAb, neonatal T cell IL-2 production remained lower than in adults. In contrast, enhancement of IL-2 mRNA expression in neonates was similar to adult levels. Anti-CD28 MoAb costimulation increased NF kappa B levels in neonates, albeit to levels lower than that of adults. The cellular mechanism governing the diminished proliferative response of neonatal T lymphocytes to anti-CD2 may therefore be due to decreased NF kappa B induction, reduced IL-2 mRNA expression and deficient IL-2 production. Although anti-CD28 MoAb costimulation enhances all of the above signals, NF kappa B and IL-2 levels remain lower than in adults, suggesting the need for further activation requirements in the neonate.
