No abstract is provided for this article.
Conference Article| February 01 1997 Molecular Mechanisms Underlying the Actions of the Pro-inflammatory Cytokine Interleukin I L. A. J. O'Neill L. A. J. O'Neill 1Department of Biochemistry, Trinity College Dublin, Ireland Search for other works by this author on: This Site PubMed Google Scholar Biochem Soc Trans (1997) 25 (1): 295–302. https://doi.org/10.1042/bst0250295 Article history Received: August 15 1996 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 L. A. J. O'Neill; Molecular Mechanisms Underlying the Actions of the Pro-inflammatory Cytokine Interleukin I. Biochem Soc Trans 1 February 1997; 25 (1): 295–302. doi: https://doi.org/10.1042/bst0250295 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: IL, interleukin, IL1RA, IL1 receptor antagonist, IL1RI, type I IL1 receptor, IL1RII, type II IL1 receptor, MAP, mitogen-activated protein, NFκB, nuclear factor κB, TNF, tumour necrosis factor This content is only available as a PDF. © 1997 Biochemical Society1997 Article PDF first page preview Close Modal You do not currently have access to this content.
Conference Article| May 01 1997 INDUCTION OF THE ADHESION MOLECULE CD44 BY THE PRO-INFLAMMATORY CYTOKINE INTERLEUKIN-1 IN ENDOTHELIAL CELLS KATHERINE FITZGERALD; KATHERINE FITZGERALD 1Department of Biochemistry & Biotechnology Institute, Trinity College, Dublin 2, Ireland Search for other works by this author on: This Site PubMed Google Scholar LUKE A.J. O'NEILL LUKE A.J. O'NEILL 1Department of Biochemistry & Biotechnology Institute, Trinity College, Dublin 2, Ireland Search for other works by this author on: This Site PubMed Google Scholar Biochem Soc Trans (1997) 25 (2): 185S. https://doi.org/10.1042/bst025185s 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 KATHERINE FITZGERALD, LUKE A.J. O'NEILL; INDUCTION OF THE ADHESION MOLECULE CD44 BY THE PRO-INFLAMMATORY CYTOKINE INTERLEUKIN-1 IN ENDOTHELIAL CELLS. Biochem Soc Trans 1 May 1997; 25 (2): 185S. doi: https://doi.org/10.1042/bst025185s 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: IL-1, interleukin-1, IL-1 RA, interleukin-1 receptor antagonist, PMA, phorbol 12-meristate 13-acetate, TNF, tumour necrosis factor, HRP, horse radish peroxidase This content is only available as a PDF. © 1997 Biochemical Society1997 Article PDF first page preview Close Modal You do not currently have access to this content.
In innate immune cells, TCA cycle components are not simply inert metabolites, but are key signaling molecules that can modulate inflammatory responses. Itaconate, an immunometabolite made by the enzyme aconitase decarboxylase (encoded by the gene Irg1), is highly upregulated in classically activated M1 macrophages and regulates immune responses by dampening inflammation. The role of itaconate in activation of alternative macrophage programs is of interest, as itaconate has recently been shown to be taken up by M2 macrophages. Here, we show that expression of Irg1 is specific to M1 macrophages and opposes regulators of IL-4 mediated alternative activation. Overexpression of Irg1 in murine M2 macrophages inhibited their program. Similarly, exogenous addition of a cell-permeable derivative of itaconate inhibited M2 gene expression and blocked activation of Stat6 and AKT in IL-4 activated macrophages. Itaconate-treated M2 macrophages also showed decreased oxidative phosphorylation, altogether suggesting that itaconate constrains IL-4-mediated alternative activation of macrophages. Mechanistically, this novel role of itaconate was not through previously reported pathways Nrf2 or Complex II (SDH), but rather via inhibition of the phosphorylation of Janus Kinase 1. We also show that an M2-specific microRNA, miR-378a, targets Irg1 to prevent itaconate production in these cells. Thus, we demonstrate that itaconate antagonizes M2 macrophage activation, suggesting a mechanism by which M1 macrophages inhibit alternative macrophage polarization. This may be useful in considering the therapeutic potential of itaconate as an inhibitor of M2 macrophages in such conditions as allergic asthma and fibrosis.
The activation of the NLRP3 inflammasome leads to the autocleavage and activation of caspase‐1. Caspase‐1 cleaves several substrates, including the pro‐inflammatory cytokine IL ‐1 β . Inflammation, in particular IL ‐1 β , has long been associated with the progression of metabolic disorders, and recent evidence suggests that the NLRP3 inflammasome plays a critical role in this inflammation. This review concentrates on the activation of NLRP3 during the development of metabolic disorders and the effect this activation has on the inflammatory state as well as the metabolic state of the cell.
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The tyrosine kinase inhibitor herbimycin A was found to block NF-κB stimulation in response to interleukin-1 and phorbol 12-myristate 13-acetate in EL4.NOB-1 thymoma cells and phorbol 12-myristate 13-acetate in Jurkat T lymphoma cells. The effect appeared not to involve inhibition of tyrosine kinase activation as neither interleukin-1 nor phorbol 12-myristate 13-acetate induced major changes in tyrosine phosphorylation in EL4.NOB-1 or Jurkat cells, respectively. Herbimycin A did not interfere with IκB-α degradation, and in unstimulated cells, it modified NF-κB prior to chemical dissociation with sodium deoxycholate. Because herbimycin A is thiol-reactive, we suspected that the target was the p50 subunit of NF-κB, which has a key thiol at cysteine 62. Herbimycin A inhibited DNA binding when added to nuclear extracts prepared from stimulated cells, which were shown to contain high levels of p50. Incubation of herbimycin A with 2-mercaptoethanol attenuated the effect. Herbimycin A was also shown to react directly with p50, blocking its ability to bind to the NF-κB consensus sequence. However, a mutant form of p50 in which cysteine 62 was mutated to serine was insensitive to herbimycin A. Finally, we demonstrated that the compound inhibited the expression of interleukin-2 (an NF-κB-regulated gene) in EL4.NOB-1 cells. These data therefore suggest that herbimycin A inhibits NF-κB by modifying the p50 subunit on cysteine 62 in the NF-κB complex, which blocks DNA binding and NF-κB-driven gene expression. The results urge caution in the use of herbimycin A as a specific tyrosine kinase inhibitor and suggest that the development of agents that selectively modify p50 may have potential as a means of inhibiting NF-κB-dependent gene transcription.
IL-1β is a potent pro-inflammatory cytokine and its production is tightly controlled by the inflammasomes. For example, the inflammasome that forms around the cytosolic receptor NLRP3 is regulated on many different levels. NLRP3 is triggered by an array of endogenous and exogenous cellular stresses and although the precise mechanism of activation is still little understood, a range of cellular signals, such as calcium signaling and reactive oxygen species, can influence the process. In addition, NLRP3 is regulated transcriptionally by the TLR pathway and by post-translational modifications such as nitrosylation and ubiquitination. We have found that NLRP3 is also post-transcriptionally regulated by a microRNA, miRNA-223. This is important during myeloid differentiation, where miR-223 is differentially expressed. We also found that the NLRP3 3′ untranslated region (UTR) is responsive to LPS and PMA, indicating a post-transcriptional component of the ‘priming signal’. Interestingly, the human NLRP3 mRNA is alternatively polyadenylated, resulting in 3′UTR isoforms of varying length. This enables selective use of regulatory elements by expressing shorter isoforms. Furthermore, in both mouse and human cells, the NLRP3 message is very unstable, which would suggest control by destabilizing RNA binding proteins. These findings provide added insights into control of this important pro-inflammatory system, can help explain cell type-specific expression of NLRP3 and might potentially provide new opportunities to interfere with inflammasome activation in disease such as Type 2 diabetes.
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 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 (termed 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 the Toll-like receptors TLR-2 and TLR-4, which bind molecules from Gram-positive and Gram-negative bacteria, respectively. 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 IL-18R and TLR-4. The receptor superfamily is evolutionarily conserved; members occur in plants and insects and also function in host defense. The signaling proteins activated are also conserved across species. This receptor superfamily therefore represents an ancient signaling system that is a critical determinant of the innate immune and inflammatory responses.
