Browse
Submit Data
Databases
API
Help

Dataset Information

21 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Interferon-dependent IL-10 production by Tregs limits tumor Th17 inflammation.

ABSTRACT: The capacity of IL-10 and Tregs in the inflammatory tumor microenvironment to impair anticancer Th1 immunity makes them attractive targets for cancer immunotherapy. IL-10 and Tregs also suppress Th17 activity, which is associated with poor prognosis in several cancers. However, previous studies have overlooked their potential contribution to the regulation of pathogenic cancer-associated inflammation. In this study, we investigated the origin and function of IL-10–producing cells in the tumor microenvironment using transplantable tumor models in mice. The majority of tumor-associated IL-10 was produced by an activated Treg population. IL-10 production by Tregs was required to restrain Th17-type inflammation. Accumulation of activated IL-10+ Tregs in the tumor required type I IFN signaling but not inflammatory signaling pathways that depend on TLR adapter protein MyD88 or IL-12 family cytokines. IL-10 production limited Th17 cell numbers in both spleen and tumor. However, type I IFN was required to limit Th17 cells specifically in the tumor microenvironment, reflecting selective control of tumor-associated Tregs by type I IFN. Thus, the interplay of type I IFN, Tregs, and IL-10 is required to negatively regulate Th17 inflammation in the tumor microenvironment. Therapeutic interference of this network could therefore have the undesirable consequence of promoting Th17 inflammation and cancer growth.

SUBMITTER: Stewart CA

PROVIDER: S-EPMC3809773 | biostudies-literature | 2013 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

RORγt Represses IL-10 Production in Th17 Cells To Maintain Their Pathogenicity in Inducing Intestinal Inflammation.

Project description:The role of retinoid-related orphan receptor γ t (RORγt) in Th17 cell differentiation has been well established; however, how it regulates other T cell lineages is still not clearly understood. In this study, we report that in mice, while promoting Th17 cell differentiation, RORγt inhibited IL-10 production by T cells, thereby preserving the pathogenicity of Th17 cells. Treatment with RORγt-specific inhibitor suppressed Th17 cell signature cytokines, but promoted IL-10 production. RORγt inhibitor-treated Th17 cells induce less severe colitis compared with control Th17 cells. Mechanistically, the RORγt inhibitor induced T cell expression of Blimp-1 (encoded by Prdm1). Prdm1-/- T cells produced significantly fewer IL-10 when treated with RORγt inhibitor compared with wild-type T cells. Furthermore, RORγt inhibitor-treated Prdm1-/- Th17 cells induce more severe colitis compared with RORγt inhibitor-treated wild-type Th17 cells. Collectively, our studies reveal a novel mechanism by which RORγt drives and maintains pathogenic Th17 cell development by inhibiting IL-10 production.

| S-EPMC6310078 | biostudies-literature

Adipocyte autophagy limits gut inflammation by controlling oxylipin and IL-10.

Project description:Lipids play a major role in inflammatory diseases by altering inflammatory cell functions, either through their function as energy substrates or as lipid mediators such as oxylipins. Autophagy, a lysosomal degradation pathway that limits inflammation, is known to impact on lipid availability, however, whether this controls inflammation remains unexplored. We found that upon intestinal inflammation visceral adipocytes upregulate autophagy and that adipocyte-specific loss of the autophagy gene Atg7 exacerbates inflammation. While autophagy decreased lipolytic release of free fatty acids, loss of the major lipolytic enzyme Pnpla2/Atgl in adipocytes did not alter intestinal inflammation, ruling out free fatty acids as anti-inflammatory energy substrates. Instead, Atg7-deficient adipose tissues exhibited an oxylipin imbalance, driven through an NRF2-mediated upregulation of Ephx1. This shift reduced secretion of IL-10 from adipose tissues, which was dependent on the cytochrome P450-EPHX pathway, and lowered circulating levels of IL-10 to exacerbate intestinal inflammation. These results suggest an underappreciated fat-gut crosstalk through an autophagy-dependent regulation of anti-inflammatory oxylipins via the cytochrome P450-EPHX pathway, indicating a protective effect of adipose tissues for distant inflammation.

| S-EPMC10015370 | biostudies-literature

Glycosylation-dependent modulation of the IL-2 signaling axis determines Th17 differentiation and IL-10 production

Project description:Metabolism plays an essential role in shaping Th cell responses including the production of pro-inflammatory cytokines. However, its effect on the production of the anti-inflammatory cytokine IL-10 has not been investigated. We show here that the glucose analogue 2-deoxyglucose (2DG) specifically inhibited Th1 and Th2 cell differentiation and accompanying IL-10 production. In contrast, 2DG promoted IL-17A production by Th17 cells, even in the presence of IL-2 known to limit Th17 differentiation, whilst simultaneously also abrogating the production of IL-10. Rather than inhibiting glycolysis, 2DG was found to act through the inhibition of glycosylation, itself critical for IL-2Ra surface expression and downstream signaling, explaining the reciprocal effect of 2DG on the Th1 and Th2 versus Th17 differentiation. The essential role of IL-2 for IL-10 production by Th17 cells was confirmed by adding IL-2 or anti-IL-2, neither of which made the cells more pathogenic. The molecular mechanism of the IL-2 driven Th17 IL-10 production may be attributed to the transcription factor c-Maf, whose expression was significantly upregulated in the presence of IL-2 signaling. The overall RNA signature of sorted IL-10+ T cells driven by IL-2, be it IL-17A+ or IL-17A-, was dominated by protein synthesis whereas that of their IL-10- counterparts by cell cycle associated processes suggesting that IL-10 secreting Th17 cells trade off self-renewal for secretory capacity. Our study thus reveals a previously unappreciated, anti-inflammatory role for IL-2 in Th17 cell production of IL-10 and identifies a novel mechanism to limit Th17 pathogenicity.

2020-03-29 | GSE129028 | GEO

CD45Rb-low effector T cells require IL-4 to induce IL-10 in FoxP3 Tregs and to protect mice from inflammation.

Project description:CD4+ effector/memory T cells (Tem) represent a leading edge of the adaptive immune system responsible for protecting the body from infection, cancer, and other damaging processes. However, a subset of Tem cells with low expression of CD45Rb (RbLoTem) has been shown to suppress inflammation despite their effector surface phenotype and the lack of FoxP3 expression, the canonical transcription factor found in most regulatory T cells. In this report, we show that RbLoTem cells can suppress inflammation by influencing Treg behavior. Co-culturing activated RbLoTem and Tregs induced high expression of IL-10 in vitro, and conditioned media from RbLoTem cells induced IL-10 expression in FoxP3+ Tregs in vitro and in vivo, indicating that RbLoTem cells communicate with Tregs in a cell-contact independent fashion. Transcriptomic and multi-analyte Luminex data identified both IL-2 and IL-4 as potential mediators of RbLoTem-Treg communication, and antibody-mediated neutralization of either IL-4 or CD124 (IL-4R?) prevented IL-10 induction in Tregs. Moreover, isolated Tregs cultured with recombinant IL-2 and IL-4 strongly induced IL-10 production. Using house dust mite (HDM)-induced airway inflammation as a model, we confirmed that the in vivo suppressive activity of RbLoTem cells was lost in IL-4-ablated RbLoTem cells. These data support a model in which RbLoTem cells communicate with Tregs using a combination of IL-2 and IL-4 to induce robust expression of IL-10 and suppression of inflammation.

| S-EPMC6533033 | biostudies-literature

B cell-derived GABA elicits IL-10+ macrophages and limits anti-tumor immunity

Project description:Small, soluble metabolites are not only essential intermediates in intracellular biochemical processes, but can also influence neighboring cells when released into the extracellular milieu. Here, we identify the metabolite and neurotransmitter GABA as a candidate signaling molecule synthesized and secreted by activated B cells and plasma cells. We show that B cell-derived GABA promotes monocyte differentiation into anti-inflammatory macrophages which secrete IL-10 and inhibit CD8+ T cell killer function. In mice, B cell deficiency or B cell-specific inactivation of the GABA generating enzyme GAD67 enhances anti-tumor responses. Our study reveals that in addition to cytokines and membrane proteins, small metabolites derived from B lineage cells have immunoregulatory functions, which may be pharmaceutical targets allowing fine-tuning of immune responses.

2021-11-15 | PXD028403 | Pride

Th17 Polarization under Hypoxia Results in Increased IL-10 Production in a Pathogen-Independent Manner.

Project description:The IL-17-producing CD4+ T helper cell (Th17) differentiation is affected by stimulation of the aryl hydrocarbon receptor (AhR) pathway and by hypoxia-inducible factor 1 alpha (HIF-1α). In some cases, Th17 become non-pathogenic and produce IL-10. However, the initiating events triggering this phenotype are yet to be fully understood. Here, we show that such cells may be differentiated at low oxygen and regardless of AhR ligand treatment such as cigarette smoke extract. Hypoxia led to marked alterations of the transcriptome of IL-10-producing Th17 cells affecting genes involved in metabolic, anti-apoptotic, cell cycle, and T cell functional pathways. Moreover, we show that oxygen regulates the expression of CD52, which is a cell surface protein that has been shown to suppress the activation of other T cells upon release. Taken together, these findings suggest a novel ability for Th17 cells to regulate immune responses in vivo in an oxygen-dependent fashion.

| S-EPMC5474482 | biostudies-literature

Gpr109a Limits Microbiota-Induced IL-23 Production To Constrain ILC3-Mediated Colonic Inflammation.

Project description:A set of coordinated interactions between gut microbiota and the immune cells surveilling the intestine play a key role in shaping local immune responses and intestinal health. Gpr109a is a G protein-coupled receptor expressed at a very high level on innate immune cells and previously shown to play a key role in the induction of colonic regulatory T cells. In this study, we show that Gpr109a-/-Rag1-/- mice exhibit spontaneous rectal prolapse and colonic inflammation, characterized by the presence of an elevated number of IL-17-producing Ror?t+ innate lymphoid cells (ILCs; ILC3). Genetic deletion of Ror?t alleviated the spontaneous colonic inflammation in Gpr109a-/-Rag1-/- mice. Gpr109a-deficient colonic dendritic cells produce higher amounts of IL-23 and thereby promote ILC3. Moreover, the depletion of gut microbiota by antibiotics treatment decreased IL-23 production, ILC3, and colonic inflammation in Gpr109a-/-Rag1-/- mice. The ceca of Gpr109a-/-Rag1-/- mice showed significantly increased colonization by members of Bacteroidaceae, Porphyromonadaceae, Prevotellaceae, Streptococcaceae, Christensenellaceae, and Mogibacteriaceae, as well as IBD-associated microbiota such as Enterobacteriaceae and Mycoplasmataceae, compared with Rag1-/- mice, housed in a facility positive for Helicobacter and murine norovirus. Niacin, a Gpr109a agonist, suppressed both IL-23 production by colonic DCs and ILC3 number in a Gpr109a-dependent manner. Collectively, our data present a model suggesting that targeting Gpr109a will be potentially beneficial in the suppression of IL-23-mediated immunopathologies.

| S-EPMC5893356 | biostudies-literature

Interferon-? regulates the production of IL-10 by toll-like receptor-activated microglia.

Project description:Pattern recognition receptors, such as toll-like receptors (TLRs), perceive tissue alterations and initiate local innate immune responses. Microglia, the resident macrophages of the brain, encode TLRs which primary role is to protect the tissue integrity. However, deregulated activation of TLRs in microglia may lead to chronic neurodegeneration. This double role of microglial responses is often reported in immune-driven neurologic diseases, as in multiple sclerosis (MS). Consequently, strategies to manipulate microglia inflammatory responses may help to ameliorate disease progression. In this context, the anti-inflammatory cytokine interleukin (IL)-10 appears as an attractive target. In this study, we investigated how activation of microglia by TLRs with distinct roles in MS impacts on IL-10 production. We found that activation of TLR2, TLR4, and TLR9 induced the production of IL-10 to a greater extent than activation of TLR3. This was surprising as both TLR3 and IL-10 play protective roles in animal models of MS. Interestingly, combination of TLR3 triggering with the other TLRs, enhanced IL-10 through the modulation of its transcription, via interferon (IFN)-?, but independently of IL-27. Thus, in addition to the modulation of inflammatory responses of the periphery described for the axis TLR3/IFN-?, we now report a direct modulation of microglial responses. We further show that the presence of IFN-? in the microenvironment abrogated the modulation of IL-10 by TLR3, whereas that of IL-17 had no effect. Considering the therapeutic application of IFN-? in MS, our study bears important implications for the understanding of the cytokine network regulating microglia responses in this setting.

| S-EPMC7165667 | biostudies-literature

Th17 can regulate silica-induced lung inflammation through an IL-1β-dependent mechanism.

Project description:Silicosis is an occupational lung disease caused by the inhalation of silica dust and characterized by lung inflammation and fibrosis. Interleukin (IL)-1β is induced by silica and functions as the key pro-inflammatory cytokine in this process. The Th17 response, which is induced by IL-1β, has been reported very important in chronic human lung inflammatory diseases. To elucidate the underlying mechanisms of IL-1β and IL-17 in silicosis, we used anakinra and an anti-IL-17 monoclonal antibody (mAb) to block the receptor of IL-1β (IL-RI) and IL-17, respectively, in a mouse model of silicosis. We observed increased IL-1β expression and an enhanced Th17 response after silica instillation. Treatment with an IL-1 type I receptor (IL-1RI) antagonist anakinra substantially decreased silica-induced lung inflammation and the Th17 response. Lung inflammation and the accumulation of inflammatory cells were attenuated in the IL-17-neutralized silicosis group. IL-17 may promote lung inflammation by modulating the differentiation of Th1 and regulatory T cells (Tregs) and by regulating the production of IL-22 and IL-1β during the lung inflammation of silicosis. Silica may induce IL-1β production from alveolar macrophages and promote inflammation by initiating a Th17 response via an IL-1β/IL-1RI-dependent mechanism. The Th17 response could induce lung inflammation during the pathogenesis of silicosis by regulating the homoeostasis of the Th immune responses and affecting the production of IL-22 and IL-1β. This study describes a potentially important inflammatory mechanism of silicosis that may bring about novel therapies for this inflammatory and fibrotic disease.

| S-EPMC4196653 | biostudies-literature

Cutting Edge: Ezrin Regulates Inflammation by Limiting B Cell IL-10 Production.

Project description:IL-10 produced by B cells is important for controlling inflammation, thus underscoring the need to identify mechanisms regulating its production. In this study, we demonstrate that conditional deletion of ezrin in B cells increases IL-10 production induced by TLR4 ligation. The MyD88-independent Toll/IL-1R domain-containing adapter inducing IFN-?-IFN regulatory factor 3 pathway is required for Ezrin-deficient B cells to produce higher IL-10 upon LPS stimulation. Treatment of B cells with a novel small-molecule inhibitor of ezrin induces its dephosphorylation and increases LPS-induced NF-?B and IFN regulatory factor 3 activation and IL-10 secretion, indicating a role for threonine 567 phosphorylation of ezrin in limiting IL-10. Loss of ezrin in B cells results in dampened proinflammatory response to a sublethal dose of LPS in vivo, which is dependent on increased IL-10 production. Taken together, our data yield new insights into molecular and membrane-cytoskeletal regulation of B cell IL-10 production and reveal ezrin as a potential therapeutic target in inflammatory diseases.

| S-EPMC4707057 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data