High affinity “peripheral-type” benzodiazepine binding sites were detected in an interleukin-1 (IL-1) responsive murine thymoma cell line EL4.NOB-1. Exposure of these cells to IL-1 over a period of at least 24 hr resulted in down-regulation of the binding sites. This effect was inhibited by the IL-1 receptor antagonist (IL-1RA) which in these cells inhibits IL-1 binding to the type I IL-1 receptor. Phorbol myristate acetate (PMA), another activator of EL4.NOB-1 cells, had an opposite effect to IL-1 in that it increased binding site expression dramatically suggesting different mechanisms of action for these two effectors. IL-1 produced a similar response in the rat glioma cell line C6 whereas PMA was ineffective. Such modulation of the peripheral-type benzodiazepine receptor may provide an insight into its physiological role and its possible participation in IL-1 actions in different cells.
Levels of the pro-inflammatory cytokine interleukin-1β are known to be elevated in patients with chronic disorders such as Alzheimer's disease. We have investigated the effects of interleukin-1β on long-term potentiation and N-methyl-d-aspartate receptor-mediated field potentials in the rat dentate gyrus in vitro utilizing field extracellular recordings obtained from the middle third of the molecular layer of the dentate gyrus. Presynaptic stimulation was applied to the commissural/association pathway at a frequency of 0.05Hz and at a distance of 50μm from the granule cell body layer. As previously reported, interleukin-1β (1ng/ml) caused an inhibition of long-term potentiation (108±2% of baseline 1h following application of tetanic stimulation compared with 145±5% in vehicle control slices). This action of interleukin-1β on long-term potentiation, as well as an inhibition of N-methyl-d-aspartate receptor-mediated field potentials, was attenuated by pre-treatment of slices with the p38 mitogen-associated protein kinase inhibitor SB203580 (1μM). SB203580 alone had no significant affect on long-term potentiation, but did cause an increase in baseline synaptic transmission [107±2% of baseline, 1h after SB203580 (1μM) treatment]. The p42/44 mitogen-activated protein kinase cascade inhibitor PD98059 (50μM) did not inhibit the interleukin-1β-induced inhibition of N-methyl-d-aspartate receptor-mediated field potentials. The cyclooxygenase inhibitor indomethacin (50μM) was found to attenuate the interleukin-1β-induced effects on both long-term potentiation and N-methyl-d-aspartate receptor-mediated field potentials. The lipid second messenger analogue C2 ceramide (20μM) was found to attenuate the expression of long-term potentiation (108±3% of baseline 1h following tetanic stimulation), and this effect was not blocked by pre-treatment with SB203580. To investigate a possible role for interleukin-1β in the normal expression of long-term potentiation, the interleukin-1 receptor antagonist (25ng/ml) was applied during the maintenance phase of long-term potentiation. This was found to depress the sustained expression of long-term potentiation (116±6% of baseline 1h following tetanic stimulation). Our results indicate possible signalling mechanisms by which interleukin-1β at pathophysiological concentrations may serve to inhibit long-term potentiation, and also suggests a role for IL-1β in the physiological expression of synaptic plasticity in the rat dentate gyrus in vitro.
No abstract is provided for this article.
Summary Over the past decade, there has been a surge in discoveries of how metabolic pathways regulate immune cell function in health and disease, establishing the field of immunometabolism. Specifically, pathways such as glycolysis, the tricarboxylic acid (TCA) cycle, and those involving lipid metabolism have been implicated in regulating immune cell function. Viral infections cause immunometabolic changes which lead to antiviral immunity, but little is known about how metabolic changes regulate interferon responses. Interferons are critical cytokines in host defense, rapidly induced upon pathogen recognition, but are also involved in autoimmune diseases. This review summarizes how metabolic change impacts interferon production. We describe how glycolysis, lipid metabolism (specifically involving eicosanoids and cholesterol), and the TCA cycle‐linked intermediates itaconate and fumarate impact type I interferons. Targeting these metabolic changes presents new therapeutic possibilities to modulate type I interferons during host defense or autoimmune disorders.
Krebs cycle intermediates traditionally link to oxidative phosphorylation whilst also making key cell components. It is now clear that some of these metabolites also act as signals. Succinate plays an important role in inflammatory, hypoxic, and metabolic signaling, while itaconate (from another Krebs cycle intermediate, cis-aconitate) has an anti-inflammatory role.
No abstract is provided for this article.
The electron transport chain (ETC) couples oxidative phosphorylation (OXPHOS) with ATP synthase to drive the generation of ATP. In immune cells, research surrounding the ETC has drifted away from bioenergetics since the discovery of cytochrome c (Cyt c) release as a signal for programmed cell death. Complex I has been shown to generate reactive oxygen species (ROS), with key roles identified in inflammatory macrophages and T helper 17 cells (TH17) cells. Complex II is the site of reverse electron transport (RET) in inflammatory macrophages and is also responsible for regulating fumarate levels linking to epigenetic changes. Complex III also produces ROS which activate hypoxia-inducible factor 1-alpha (HIF-1α) and can participate in regulatory T cell (Treg) function. Complex IV is required for T cell activation and differentiation and the proper development of Treg subsets. Complex V is required for TH17 differentiation and can be expressed on the surface of tumor cells where it is recognized by anti-tumor T and NK cells. In this review, we summarize these findings and speculate on the therapeutic potential of targeting the ETC as an anti-inflammatory strategy.
Every organism has to contend with the risk of infection. To cope, organisms have evolved two types of immune responses: the more recent “adaptive” system, found only in vertebrates; and the more ancient “innate” system, which is present in both plants and animals. Researchers have uncovered remarkable evolutionary conservation of innate immune mechanisms between plants and animals (see the figure). They use similar receptor molecules to sense pathogens, for example, and for immune system signaling. On page 1439 of this issue, Lu et al. (1) detail how one plant cell receptor that senses bacterial flagellin triggers an innate immune response. They describe how the activity of the Arabidopsis flagellin-sensing receptor 2 (FLS2) is attenuated by a posttranslational modification process called ubiquitination and subsequent degradation. The research offers insight into the general workings of innate immunity and shows that FLS2 activity has clear parallels to the activity of Toll-like receptors (TLRs), an important class of innate immune system receptors. It also indicates that genetic modification to enhance disease resistance in plants is a practical possibility.
Immunometabolism has emerged as a key focus for immunologists, with metabolic change in immune cells becoming as important a determinant for specific immune effector responses as discrete signaling pathways. A key output for these changes involves post-translational modification (PTM) of proteins by metabolites. Products of glycolysis and Krebs cycle pathways can mediate these events, as can lipids, amino acids, and polyamines. A rich and diverse set of PTMs in macrophages and T cells has been uncovered, altering phenotype and modulating immunity and inflammation in different contexts. We review the recent findings in this area and speculate whether they could be of use in the effort to develop therapeutics for immune-related diseases.
Bacterial lipopolysaccharide (LPS) stimulation of macrophages and inflammation via the Toll-like receptor 4 (TLR4) signaling pathway through NF-κΒ generates reactive oxygen species (ROS) and proinflammatory cytokines such as IL-1β, IL-6, and TNFα. Because glutathione transferase Omega 1-1 (GSTO1-1) can catalyze redox reactions such as the deglutathionylation of proteins and has also been implicated in the release of IL-1β we investigated its role in the development of LPS-mediated inflammation. Our data show that shRNA knockdown of GSTO1-1 in macrophage-like J774.1A cells blocks the expression of NADPH oxidase 1 and the generation of ROS after LPS stimulation. Similar results were obtained with a GSTO1-1 inhibitor. To maintain high ROS levels during an inflammatory response, LPS stimulation causes the suppression of enzymes such as catalase and glutathione peroxidase that protect against oxidative stress. The knockdown of GSTO1-1 also attenuates this response. Our data indicate that GSTO1-1 needs to be catalytically active and mediates its effects on the LPS/TLR4 inflammatory pathway upstream of NF-κΒ. These data suggest that GSTO1-1 is a novel target for anti-inflammatory intervention.
A repertoire of 10 TLRs mediate the first response to all microbes that infect mammals. They are the long sought receptors for a wide range of microbial products. Notable examples include TLR4 which r
No abstract is provided for this article.
No abstract is provided for this article.
The innate immune system is the primary line of defence against invading pathogenic microbes. Toll-like receptors (TLRs) are a family of membrane receptors which play a pivotal role in sensing a wide range of invading pathogens including bacteria, fungi and viruses. TLR-deficient mice have provided us with immense knowledge on the functioning of individual TLRs. Dysregulation of TLR signalling is linked with a number of disease conditions. Disease models have helped show that targeting components of TLR signalling cascades could lead to novel therapies in the treatment of infectious diseases. In this review we focus on the evidence provided to date to explain just how important TLRs are in host defence against microbial pathogens.
The growing field of immunometabolism has taught us how metabolic cellular reactions and processes not only provide a means to generate ATP and biosynthetic precursors, but are also a way of controlling immunity and inflammation. Metabolic reprogramming of immune cells is essential for both inflammatory as well as anti-inflammatory responses. Four anti-inflammatory therapies, DMF, Metformin, Methotrexate and Rapamycin all work by affecting metabolism and/or regulating or mimicking endogenous metabolites with anti-inflammatory effects. Evidence is emerging for the targeting of specific metabolic events as a strategy to limit inflammation in different contexts. Here we discuss these recent developments and speculate on the prospect of targeting immunometabolism in the effort to develop novel anti-inflammatory therapeutics. As accumulating evidence for roles of an intricate and elaborate network of metabolic processes, including lipid, amino acid and nucleotide metabolism provides key focal points for developing new therapies, we here turn our attention to glycolysis and the TCA cycle to provide examples of how metabolic intermediates and enzymes can provide potential novel therapeutic targets.
