The discovery of the Toll-like receptors (TLRs) has revolutionised the field of innate immunity. One unresolved question regarding LPS signalling is whether there is a role for tyrosine kinases downstream of the LPS receptor. Studies in mice deficient in Bruton’s tyrosine kinase have previously shown that they are defective in their responses to LPS. Further investigation into the role of Btk in LPS signalling has directly implicated Btk downstream of TLR4, both with respect to p38 MAPK activation and activation of the transcription factor NFκB. In fact Btk is activated by LPS and has been shown to directly bind TLR4 and the key proximal signalling proteins involved in LPS-induced NFκB activation, MyD88, Mal and IRAK-1. These recent findings point to a direct role for Btk in LPS signal transduction and raise interesting questions regarding the mode of activation of Btk following LPS stimulation and the precise nature of the pathways activated downstream of Btk. A better understanding of how Btk functions in LPS signalling will have important implications for inflammatory and autoimmune disorders and therapies thereof.
Conference Abstract| November 01 1996 DAUNORUBICIN ACTIVATES NFkB AND POTENTIATES TNF-INDUCED GENE EXPRESSION Marion P. Boland; Marion P. Boland 1Inflammation Group, Department of Biochemistry, Trinity College, Dublin 2 Search for other works by this author on: This Site PubMed Google Scholar Luke A.J. O'Neill Luke A.J. O'Neill 1Inflammation Group, Department of Biochemistry, Trinity College, Dublin 2 Search for other works by this author on: This Site PubMed Google Scholar Biochem Soc Trans (1996) 24 (4): 601S. https://doi.org/10.1042/bst024601sb Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Share Icon Share Twitter LinkedIn Cite Icon Cite Get Permissions Citation Marion P. Boland, Luke A.J. O'Neill; DAUNORUBICIN ACTIVATES NFkB AND POTENTIATES TNF-INDUCED GENE EXPRESSION. Biochem Soc Trans 1 November 1996; 24 (4): 601S. doi: https://doi.org/10.1042/bst024601sb Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search Search nav search search input Search input auto suggest search filter 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.
The field of immunometabolism has demonstrated that metabolites can lead double lives as immunomodulators. Itaconate is perhaps the best example of such a moonlighting molecule, and has been shown to have multiple anti-inflammatory effects in macrophages. Itaconate is significantly upregulated under inflammatory conditions, and can promote an anti-inflammatory phenotype by reducing oxidative stress and blocking transcriptional responses to lipopolysaccharide (LPS) in murine macrophages. Antibacterial and protumor effects have also been described for itaconate and, most recently, reports have surfaced of its possible modulatory roles during Zika virus infection in murine neurons. We posit here that itaconate is a crucial determinant of innate immune responses, and may potentially be harnessed therapeutically to treat inflammatory diseases.
No abstract is provided for this article.
Expression of the micro RNA miR‐223 is deregulated during influenza or hepatitis B infection and in inflammatory bowel disease, type 2 diabetes, leukaemia and lymphoma. Although this may also be the result of the disease per se , increasing evidence suggests a role for miR‐223 in limiting inflammation to prevent collateral damage during infection and in preventing oncogenic myeloid transformation. Validated targets for miR‐223 that have effects on inflammation and infection include granzyme B, IKK α, Roquin and STAT 3. With regard to cancer, validated targets include C/ EBP β, E2F1, FOXO 1 and NFI ‐A. The effect of miR‐223 on these targets has been documented individually; however, it is more likely that miR‐223 affects multiple targets simultaneously for key processes where the micro RNA is important. Such processes include haematopoietic cell differentiation, particularly towards the granulocyte lineage (where miR‐223 is abundant) and as cells progress down the myeloid lineage (where miR‐223 expression decreases). NF ‐κB and the NLRP 3 inflammasome are important inflammatory mechanisms that are dampened by miR‐223 in these cell types. The mi RNA can also directly target viruses such as HIV , leading to synergistic effects during infection. Here we review the recent studies of miR‐223 function to show how it modulates inflammation, infection and cancer development.
No abstract is provided for this article.
A striking change has happened in the field of immunology whereby specific metabolic processes have been shown to be a critical determinant of immune cell activation. Multiple immune receptor types rewire metabolic pathways as a key part of how they promote effector functions. Perhaps surprisingly for immunologists, the Krebs cycle has emerged as the central immunometabolic hub of the macrophage. During proinflammatory macrophage activation, there is an accumulation of the Krebs cycle intermediates succinate and citrate, and the Krebs cycle–derived metabolite itaconate. These metabolites have distinct nonmetabolic signaling roles that influence inflammatory gene expression. A key bioenergetic target for the Krebs cycle, the electron transport chain, also becomes altered, generating reactive oxygen species from Complexes I and III. Similarly, alternatively activated macrophages require α-ketoglutarate-dependent epigenetic reprogramming to elicit anti-inflammatory gene expression. In this review, we discuss these advances and speculate on the possibility of targeting these events therapeutically for inflammatory diseases.
Interleukin-1 (IL-1) is a central regulator of the immune and inflammatory responses. Recently, significant advances have been made in the area of IL-1 receptors and IL-1 signal transduction. A family of proteins has been described that share significant homology in their signaling domains with the Type I IL-1 receptor (IL-1RI). These include the IL-1 receptor accessory protein (IL-1AcP), which does not bind IL-1 but is essential for IL-1 signaling; a Drosophila protein Toll; a number of human Toll-like receptors (hTLRs); the putative IL-18/IL-1-gamma receptor IL-1Rrp (IL-1 receptor-related protein); and a number of plant proteins. All appear to be involved in host responses to injury and infection. These homologies also extend to novel signaling proteins implicated in IL-1 action. Two IL-1 receptor-associated kinases, IRAK-1 and IRAK-2, which have homologs in Drosophila (Pelle) and plants (Pto), have been implicated in the activation of the transcription factor, nuclear factor kappaB (NF-kappaB). IRAK-1 has also been implicated in AP1 induction, Jun amino-terminal kinase (JNK) activation, and IL-2 induction. It recruits the adapter protein TRAF6 to the IL-1 receptor complex via an interaction with IL-1AcP. TRAF6 then relays the signal via NF-kappaB-inducing kinase (NIK) to two I-kappaB kinases (IKK-1 and -2), leading to NF-kappaB activation. Progress has also been made on other IL-1-responsive kinases, including JNK and p38 MAP kinase, with the latter having a role in multiple responses to IL-1. The remarkable conservation between diverse species indicates that the IL-1 system represents an ancient signaling machine critical for responses to environmental stresses and attack by pathogens.
No abstract is provided for this article.
The ability of interleukin-1 (IL-1) to stimulate prostaglandin E2 (PGE2) production by human rheumatoid adherent synovial cells was found to be time-dependent and sensitive to protein synthesis inhibitors. Cells incubated with exogenous arachidonic acid (10 microM) showed no increase in PGE2 production. However, with IL-1 (2.5 U/ml) and exogenous arachidonic acid there was a marked increase, with levels reaching twice that for cells incubated with IL-1 alone. Aspirin pre-treatment studies and the use of [acetyl-14C]aspirin showed that IL-1 increased PGE2 production through the induction of cyclo-oxygenase.
