The signal transduction pathways activated by the proinflammatory cytokine interleukin-1 (IL-1) have been the focus of much attention because of the important role that IL-1 plays in inflammatory diseases. A number of proteins have been described that participate in the post-receptor activation of the transcription factor nuclear factor κB (NF-κB), and stress-activated protein kinases such as p38 mitogen-activated protein kinase (MAPK). It has also emerged that the type I IL-1 receptor (IL-1RI) is a member of an expanding receptor superfamily. These related receptors all have sequence similarity in their cytosolic regions. The family includes the Drosophila melanogaster protein Toll, the IL-18 receptor (IL-18R), and 10 Toll-like receptors (TLRs), TLR-1 to TLR-10, which bind to microbial products, activating host defense responses. Because of the similarity of IL-1RI to Toll, the conserved sequence in the cytosolic region of these proteins has been termed the Toll-IL-1 receptor (TIR) domain. The same proteins activated during signaling by IL-1RI also participate in signaling by other receptors with TIR domains. The receptor superfamily is evolutionarily conserved; members also occur in plants and insects, where they also function in host defense. The signaling proteins that are activated are also conserved across species. Differences are, however, starting to emerge in signaling pathways activated by different receptors. This receptor superfamily, therefore, represents an ancient signaling system that is a critical determinant of the innate immune and inflammatory responses.
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No abstract is provided for this article.
Innate immunity to viruses involves receptors such as RIG-I, which senses viral RNA and triggers a signalling pathway involving the outer mitochondrial membrane protein MAVS. Recent work has identified that NLRX1, a member of another class of innate immune receptors, sequesters MAVS away from RIG-I and thereby prevents mitochondrial anti-viral immunity.
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Conference Article| February 01 1996 Effect of pertussis toxin and PGE2 on the functioning of the IL-2 promoter in Interleukin-1 treated EL4. NOB-1 thymoma cells L. M. McCarthy; L. M. McCarthy 1Biochemistry Dept, Trinity College, Dublin 2, Ireland. Search for other works by this author on: This Site PubMed Google Scholar L. A. J. O'neill L. A. J. O'neill 1Biochemistry Dept, Trinity College, Dublin 2, Ireland. Search for other works by this author on: This Site PubMed Google Scholar Author and article information Publisher: Portland Press Ltd Online ISSN: 1470-8752 Print ISSN: 0300-5127 © 1996 Biochemical Society1996 Biochem Soc Trans (1996) 24 (1): 82S. https://doi.org/10.1042/bst024082s Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Facebook Twitter LinkedIn Email Cite Icon Cite Get Permissions Citation L. M. McCarthy, L. A. J. O'neill; Effect of pertussis toxin and PGE2 on the functioning of the IL-2 promoter in Interleukin-1 treated EL4. NOB-1 thymoma cells. Biochem Soc Trans 1 February 1996; 24 (1): 82S. doi: https://doi.org/10.1042/bst024082s 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 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.
Recent evidence suggests that there may be specificities in the signal transduction pathways activated by different Toll-like receptors (TLRs), with different sets of genes being induced by TLR-4 when compared with TLR-2. These differences may be because of different signalling adapters, with MyD88 being used by several TLRs, and the adapter MyD88-adapter-like (Mal) being recruited specifically by TLR-4. The set of genes being induced may be tailored for the subsequent elimination of the pathogen being recognized, as a result of differences in signal transduction pathways activated by TLRs. These findings may ultimately explain how dendritic cells control specific T-cell responses.
Summary The discovery of the NLRP 3 ( NLR family, pyrin domain containing 3) inflammasome provided an important molecular mechanism in the induction of the central pro‐inflammatory cytokine interleukin‐1β ( IL ‐1β), via activation of caspase‐1, which processes pro‐ IL ‐1β into its mature active form. IL ‐1 has long been known to exert metabolic effects, most notably being implicated in insulin resistance and obesity. A key phenotype of the NLRP 3‐deficient mouse is insulin hypersensitivity. Over the past 5 years, a number of discoveries have been made suggesting a close interplay between NLRP 3 and metabolism. Metabolic products have been shown to activate NLPR 3, and disturbed mitochondria have been shown to be involved in NLRP 3 function. It is possible that under normal physiology NLRP 3 is homeostatic and maintains the metabolic balance. However, upon chronic activation (e.g. in obesity or hypercholesterolemia), NLRP 3 becomes pathologic and promotes disease. Here, we review these findings and place them in the context of exciting new insights that are improving our understanding of the link between inflammation and metabolism. These insights are giving rise to better understanding of disease pathogenesis and might point to new therapeutic approaches.
HIF1α is a common component of pathways involved in the control of cellular metabolism and has a role in regulating immune cell effector functions. Additionally, HIF1α is critical for the maturation of dendritic cells and for the activation of T cells. HIF1α is induced in LPS-activated macrophages, where it is critically involved in glycolysis and the induction of proinflammatory genes, notably Il1b. The mechanism of LPS-stimulated HIF1α induction involves succinate, which inhibits prolyl hydroxylases (PHDs). Pyruvate kinase M2 (PKM2) is also induced and interacts with and promotes the function of HIF1α. In another critical inflammatory cell type, Th17 cells, HIF1α acts via the retinoic acid-related orphan receptor-γt (RORγt) to drive Th17 differentiation. HIF1α is therefore a key reprogrammer of metabolism in inflammatory cells that promotes inflammatory gene expression.
Signal transduction processes activated by Toll-like receptors (TLRs) include the important transcription factor NF-kappaB and 2 MAP kinases, p38 and Jun N-terminal kinase. These signals ultimately give rise to increased expression of a multitude of pro-inflammatory proteins. Receptor-proximal proteins involved in signalling by all TLRs include the adapter MyD88, 3 IRAKs (IRAK-4, IRAK and IRAK-2), Tollip, Traf-6 and TAK-1. Differences between signals generated by TLRs are emerging, with both TLR4 and TLR2 signalling requiring an additional adapter termed MyD88-adapter-like (Mal; also known as TIRAP). MyD88 and Mal both have a homologous Toll/IL-1 receptor (TIR) domain although they differ in their N-termini, with MyD88 possessing a death domain. In addition, structural models reveal marked differences in surface charges which, when taken with surface charge differences between TLR2 and TLR4 TIR domains, may indicate that TLR4 but not TLR2 recruits Mal directly. Another difference is that Mal can become phosphorylated. Future studies on Mal will reveal specificities in signal transduction by different TLRs, which may ultimately provide molecular explanations for specificities in the innate immune response to infection.
