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.
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.
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.
The effects of the cytokine, Interleukin-1β (IL-1β), and its receptor antagonist IL-1ra, were studied on long-term potentiation in the dentate gyrus of rat hippocampal slices. Field excitatory postsynaptic potentials were recorded extracellularly in the molecular region of the dentate gyrus in response to stimulation of the medial perforant path. Low frequency synaptic transmission was unaffected by IL-1β (1 ng/ml), but pre-treatment with IL-1β completely blocked induction of long-term potentiation. Co-application of IL-1β and IL-1ra (100 ng/ml) attenuated the inhibitory effect of IL-1β. In parallel with these findings, we demonstrate that IL-1fβ also inhibited 45Ca influx into the slices. The inhibitory effect of IL-1β on induction was mimicked by tumour necrosis factor (TNF; 4.5 ng/ml) and lipopolysaccharide (LPS; 10 μg/ml). These results indicate a modulatory role for cytokines in hippocampus and suggest that the inhibitory effect of IL-1β on long-term potentiation may relate to its inhibitory effect on calcium channel activity.
Succinate is an intermediate of the tricarboxylic acid (TCA) cycle, and plays a crucial role in adenosine triphosphate (ATP) generation in mitochondria. Recently, new roles for succinate outside metabolism have emerged. Succinate stabilizes the transcription factor hypoxia-inducible factor-1α (HIF-1α) in specific tumors and in activated macrophages, and stimulates dendritic cells via its receptor succinate receptor 1. Furthermore, succinate has been shown to post-translationally modify proteins. This expanding repertoire of functions for succinate suggests a broader role in cellular activation. We review the new roles of succinate and draw parallels to other metabolites such as NAD+ and citrate whose roles have expanded beyond metabolism and into signaling.
No abstract is provided for this article.
NLRP3 is a highly attractive drug target due to its implication in the pathogenesis of a number of diseases, including both monogenic NLRP3-driven disorders and more complex inflammatory disorders. Pharmacological inhibitors of NLRP3 would impact on IL-1β and IL-18 production and pyroptosis, potentially resulting in more effective antiinflammatory therapies than those targeting just IL-1. As our understanding of the molecular mechanisms underlying NLRP3 activation improves, so does our capability to design novel specific pharmacological inhibitors of the pathway. Several NLRP3 inhibitors have been reported to date and are at different stages of clinical development. This chapter will highlight the potential therapeutic opportunities targeting the different steps of NLRP3 activation, and will provide a framework for the development of future therapeutics targeting the inflammasome.
No abstract is provided for this article.
No abstract is provided for this article.
No abstract is provided for this article.
The interleukin-1 (IL-1) receptor/Tolllike receptor (TLR) superfamily is a recently defined and expanding group of receptors that participate in host responses to injury and infection. The superfamily is defined by the Toll/IL-1 receptor (TIR) domain, which occurs in the cytosolic region of family members, and is further subdivided into two groups based on homology to either the Type I IL-1 receptor or Drosophila Toll receptor extracellular domain. The former group includes the receptor for the important Th1 cytokine IL-18, and T1/ST2, which may have a role in Th2 cell function. The latter group includes six mammalian TLRs, including TLR2 and TLR4, that largely mediate the host response to gram-positive and gram-negative bacteria, respectively. Whether bacterial products are actual ligands for TLRs, or whether they generate ligands via as yet unidentified pattern recognition receptors, has yet to be determined. Signaling pathways activated via the TIR domain trigger the activation of downstream kinases, and transcription factors such as NF-κB, and involve the adaptor protein MyD88, which itself contains a TIR domain. J. Leukoc. Biol. 67: 508–514; 2000.
