The regulation of IL-10 expression

Interleukin (IL)-10 is an important immunoregulatory cytokine and an understanding of how IL-10 expression is controlled is critical in the design of immune intervention strategies. IL-10 is produced by almost all cell types within the innate (including macrophages, monocytes, dendritic cells (DCs), mast cells, neutrophils, eosinophils and natural killer cells) and adaptive (including CD4(+) T cells, CD8(+) T cells and B cells) immune systems. The mechanisms of IL-10 regulation operate at several stages including chromatin remodelling at the Il10 locus, transcriptional regulation of Il10 expression and post-transcriptional regulation of Il10 mRNA. In addition, whereas some aspects of Il10 gene regulation are conserved between different immune cell types, several are cell type- or stimulus-specific. Here, we outline the complexity of IL-10 production by discussing what is known about its regulation in macrophages, monocytes, DCs and CD4(+) T helper cells

The impact of viral mutations on recognition by SARS-CoV-2 specific T cells.

We identify amino acid variants within dominant SARS-CoV-2 T cell epitopes by interrogating global sequence data. Several variants within nucleocapsid and ORF3a epitopes have arisen independently in multiple lineages and result in loss of recognition by epitope-specific T cells assessed by IFN-γ and cytotoxic killing assays. Complete loss of T cell responsiveness was seen due to Q213K in the A∗01:01-restricted CD8+ ORF3a epitope FTSDYYQLY207-215; due to P13L, P13S, and P13T in the B∗27:05-restricted CD8+ nucleocapsid epitope QRNAPRITF9-17; and due to T362I and P365S in the A∗03:01/A∗11:01-restricted CD8+ nucleocapsid epitope KTFPPTEPK361-369. CD8+ T cell lines unable to recognize variant epitopes have diverse T cell receptor repertoires. These data demonstrate the potential for T cell evasion and highlight the need for ongoing surveillance for variants capable of escaping T cell as well as humoral immunity.This work is supported by the UK Medical Research Council (MRC); Chinese Academy of Medical Sciences(CAMS) Innovation Fund for Medical Sciences (CIFMS), China; National Institute for Health Research (NIHR)Oxford Biomedical Research Centre, and UK Researchand Innovation (UKRI)/NIHR through the UK Coro-navirus Immunology Consortium (UK-CIC). Sequencing of SARS-CoV-2 samples and collation of data wasundertaken by the COG-UK CONSORTIUM. COG-UK is supported by funding from the Medical ResearchCouncil (MRC) part of UK Research & Innovation (UKRI),the National Institute of Health Research (NIHR),and Genome Research Limited, operating as the Wellcome Sanger Institute. T.I.d.S. is supported by a Well-come Trust Intermediate Clinical Fellowship (110058/Z/15/Z). L.T. is supported by the Wellcome Trust(grant number 205228/Z/16/Z) and by theUniversity of Liverpool Centre for Excellence in Infectious DiseaseResearch (CEIDR). S.D. is funded by an NIHR GlobalResearch Professorship (NIHR300791). L.T. and S.C.M.are also supported by the U.S. Food and Drug Administration Medical Countermeasures Initiative contract75F40120C00085 and the National Institute for Health Research Health Protection Research Unit (HPRU) inEmerging and Zoonotic Infections (NIHR200907) at University of Liverpool inpartnership with Public HealthEngland (PHE), in collaboration with Liverpool School of Tropical Medicine and the University of Oxford.L.T. is based at the University of Liverpool. M.D.P. is funded by the NIHR Sheffield Biomedical ResearchCentre (BRC – IS-BRC-1215-20017). ISARIC4C is supported by the MRC (grant no MC_PC_19059). J.C.K.is a Wellcome Investigator (WT204969/Z/16/Z) and supported by NIHR Oxford Biomedical Research Centreand CIFMS. The views expressed are those of the authors and not necessarily those of the NIHR or MRC

Self-regulatory depletion in dogs: Insulin release is not necessary for the replenishment of persistence

It has been hypothesized that self-control is constrained by a limited energy resource that can be depleted through exertion. Once depleted, this resource can be replenished by the consumption or even the taste of glucose. For example, the need to inhibit reduces subsequent persistence at problem solving by humans and dogs, an effect that is not observed when a glucose drink (but not placebo) is administered following initial inhibition. The mechanism for replenishment by glucose is currently unknown. Energy transfer is not necessary, though insulin secretion may be involved. This possibility was investigated in the current study by having dogs exert self-control (sit-stay) and subsequently giving them (1) glucose that causes the release of insulin, (2) fructose that does not result in the release of insulin nor does it affect glucose levels (but is a carbohydrate), or (3) a calorie-free drink. Persistence measures indicated that both glucose and fructose replenished canine persistence, whereas the calorie-free drink did not. These results indicate that insulin release is probably not necessary for the replenishment that is presumed to be responsible for the increase in persistence.status: publishe

Acetaminophen (paracetamol) inhibits myeloperoxidase-catalyzed oxidant production and biological damage at therapeutically achievable concentrations

The heme peroxidase enzyme myeloperoxidase (MPO) is released by activated neutrophils and monocytes, where it uses hydrogen peroxide (H2O2) to catalyze the production of the potent oxidants hypochlorous acid (HOCl), hypobromous acid (HOBr) and hypothiocyanous acid (HOSCN) from halide and pseudohalide (SCN-) ions. These oxidants have been implicated as key mediators of tissue damage in many human inflammatory diseases including atherosclerosis, asthma, rheumatoid arthritis, cystic fibrosis and some cancers. It is shown here that acetaminophen (paracetamol), a phenol-based drug with analgesic and antipyretic actions, is an efficient inhibitor of HOCl and HOBr generation by isolated MPO-H2O2-halide systems. With physiological halide concentrations, acetaminophen concentrations required for 50% inhibition of oxidant formation (IC50) were 77±6μM (100mMCl-) and 92±2μM (100mMCl- plus 100μMBr-), as measured by trapping of oxidants with taurine. The IC50 for inhibition of HOCl generation by human neutrophils was ca. 100μM. These values are lower than the maximal therapeutic plasma concentrations of acetaminophen (≤150μM) resulting from typical dosing regimes. Acetaminophen did not diminish superoxide generation by neutrophils, as measured by lucigenin-dependent chemiluminescence. Inhibition of HOCl production was associated with the generation of fluorescent acetaminophen oxidation products, consistent with acetaminophen acting as a competitive substrate of MPO. Inhibition by acetaminophen was maintained in the presence of heparan sulfate and extracellular matrix, materials implicated in the sequestration of MPO at sites of inflammation in vivo. Overall, these data indicate that acetaminophen may be an important modulator of MPO activity in vivo. © 2009 Elsevier Inc