TNF-alpha and IL-17 synergize to inhibit IL-13 bioactivity via IL-13Ra2 induction in human lung fibroblasts
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE56338 | GEO | 2014/12/31
SECONDARY ACCESSION(S): PRJNA242955
REPOSITORIES: GEO
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Project description:Background: Dupilumab, a fully human monoclonal antibody that binds IL-4Ra and inhibits signaling of both IL-4 and IL-13, has shown efficacy across multiple diseases with underlying type 2 signatures and is approved for treatment of asthma, atopic dermatitis and chronic sinusitis with nasal polyposis. We sought to provide a comprehensive analysis of the redundant and distinct roles of IL-4 and IL-13 in type 2 inflammation and report dupilumab mechanisms of action. Methods: Using primary cell assays and a mouse model of house dust mite induced asthma, we compared IL-4 versus IL-13 versus IL-4Ra blockers. Results: Intranasal administration of either IL-4 or IL-13 confers an asthma-like phenotype in mice by inducing immune cell lung infiltration, including eosinophils, increasing cytokine/chemokine expression and mucus production, thus demonstrating redundant functions of these cytokines. We further teased out their respective contributions using human in vitro culture systems. Then, in a mouse asthma model by comparing in head to head studies, either IL-4 or IL-13 inhibition to dual IL-4/IL-13 inhibition, we demonstrate that blockade of both IL-4 and IL-13 is required to broadly block type 2 inflammation, which translates to protection from allergen-induced lung function impairment. Notably, only dual IL-4/IL-13 blockade prevented eosinophil infiltration into lung tissue without affecting circulating eosinophils, demonstrating that tissue, but not circulating eosinophils contribute to disease pathology. Conclusions: Overall, these data support IL-4 and IL-13 as key drivers of type 2 inflammation, and help provide insight into the therapeutic mechanism of dupilumab, a dual IL-4/IL-13 blocker, in multiple type 2 diseases.
2019-11-25 | GSE140900 | GEO
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Project description:IL-13 plays a key role during protective type 2 immune responses at mucosal sites, such as during infection with nematodes. However, dysregulation of IL-13 can also contribute to the pathogenesis of allergic and fibrotic diseases. Matrix remodelling is an important component of repair processes in the lung but is also a hallmark of chronic diseases such as asthma. Since IL-13 shares receptors and signalling pathways with IL-4, disentangling the relative contributions of these two type 2 cytokines has been challenging. Additionally, little is known about the singular role of IL-13 in more acute settings of tissue injury/repair and whether IL-13 regulates remodelling of the extracellular matrix following tissue injury. In this study, we used Nippostrongylus brasiliensis infection as model of acute lung tissue damage and repair by comparing responses between WT and IL-13-deficient mice, in which IL-4 signalling is intact.
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Project description:Interleukin (IL)-4 and IL-13 are related cytokines with well-known roles in type 2 immune response. However, their effects on neutrophils are less defined and existing research has provided somewhat contradictory results We measured IL-4-, IL-13- and IFN-g-stimulated gene expression in highly purified human neutrophils.
2023-03-28 | GSE218535 | GEO
Project description:Myelofibrosis (MF) is a disease with high unmet medical need since bone marrow transplant is not an option for many patients and JAK inhibitors are generally effective for only 2-3 years. MF is characterized by the presence of dysplastic megakaryocytes and progression to fulminant disease is associated with significantly increased fibrosis in the bone marrow. Despite evidence of an inflammatory state in MF that drives disease progression, the specific factors that promote megakaryocyte growth are poorly understood. Here, we analyzed changes in the cytokine profiles of MF mouse models before and after development of fibrosis coupled with analysis of bone marrow populations by scRNA-seq. We found high IL-13 levels in the bone marrow of MF mice. IL-13 promoted the growth of mutant megakaryocytes and induced the surface expression of TGF-B and collagen biosynthesis. Analysis of samples from patients with myelofibrosis revealed elevated levels of IL-13 in plasma and increased IL-13 receptor expression in megakaryocytes in the bone marrow, indicating that our observations in mice are relevant in human disease. In vivo, IL-13 overexpression promoted disease progression while reducing IL-13/IL-4 signaling reduced several features of the disease including fibrosis. Lastly, we found an increase in T cells and mast cells, which are known sources of IL-13 in MF bone marrow. Together, our data demonstrate that IL-13 is involved in the progression of MF and that inhibition of the IL-13/IL-4 signaling pathway should be investigated as a therapeutic option in MF.
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Project description:Tumor-associated macrophages (TAM) represent an abundant cell population of the immune infiltrate in solid tumors and have been shown to orchestrate escape from immune surveillance. Macrophages display a very plastic phenotype which is recapitulated in vitro by classifying certain subsets according to exposure with defined, individual cytokines. The tumor-promoting M2 macrophages are polarized in vitro by differentiating human monocyte-derived macrophages with the T helper cell type 2 (Th2) response cytokines interleukin-4 and interleukin-13 or the immunosuppressive cytokine interleukin-10. Notably, only the latter macrophage subset undergoes apoptosis when treated with the colony stimulating factor 1 receptor (CSF1R) blocking antibody emactuzumab. However, under physiologic conditions the phenotype of TAM is shaped by a combination of cytokines. Hence, we evaluated if the addition of IL-10 to IL-4 or IL-13 differentiated macrophages is able to override IL-4/-13 mediated signaling and to restore susceptibility to emactuzumab. Though addition of IL-10 did not restore emactuzumab susceptibility, we surprisingly detected that only IL-4 differentiated macrophages sustained their specific marker expression while IL-10 skewed the IL-13 differentiated macrophage profile towards the IL-10 regulated phenotype. In-depth characterization by gene expression profiling revealed unique signatures of IL-4+IL-10 and IL-13+IL-10 differentiated macrophage subsets characterized by upregulation of the canonical NFκB signaling or Wnt/β-catenin signaling pathways, respectively. In silico-based analysis of a large cohort of cancer patients revealed distinct interleukin-4 or interleukin-13 overexpression patterns in a subset of patients with partial co-expression of IL-10 but almost absent IL-4/IL-13 co-expression. These patients may have less TAM depletion under therapy with CSF1R inhibitors.
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Project description:This experiment aims to identify the biological pathways and diseases associated with the cytokine Interleukin 13 (IL-13) using gene expression measured in peripheral blood mononuclear cells (PBMCs). The experiment comprised of samples obtained from 3 healthy donors. The expression profiles of in vitro IL-13 stimulation were generated using RNA-seq technology for 3 PBMC samples at 24 hours. The transcriptional profiles of PBMCs without IL-13 stimulation were also generated to be used as controls. An IL-13R-alpha antagonist (Redpath et al. Biochemical Journal, 2013) was introduced into IL-13 stimulated PBMCs and the gene expression levels after 24h were profiled to examine the neutralization of IL-13 signaling by the antagonist.
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Project description:IL-4 and IL-13 are cytokines involved in type 2 immune responses involved in atopic asthma and other diseases. They have a partially overlapping set of cognate receptors whose roles are incompletely understood. Here we explore the effects of these cytokines on lung fibroblasts in order to assess the global similarities and contrasts in the genes whose expression their ligation modulates. IMR-90 lung fibroblast cells were cultured on matrigel or plastic and treated for 24 hours with IL-4 (10 ng/ml), IL-13 (10ng/ml), or TNFa (10 ng/ml) before harvest.
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Project description:Human neutrophils stimulated with IL-13.
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Project description:IL-4 and IL-13 are cytokines involved in type 2 immune responses involved in atopic asthma and other diseases. They have a partially overlapping set of cognate receptors whose roles are incompletely understood. Here we explore the effects of blocking one or both subunits of the IL-13 alpha receptor on the action of these cytokines on IMR-90 lung fibroblast cells.
2013-12-31 | GSE47527 | GEO