Interleukin 27 is a novel cytokine with anti-inflammatory effects against spondyloarthritis through the suppression of Th17 responses
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ABSTRACT:
PROVIDER: PRJEB56819 | ENA |
REPOSITORIES: ENA
Dataset's files
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| Other | ||||
| ERR10798715_1.fastq.gz | Fastqsanger.gz | |||
| ERR10798715_2.fastq.gz | Fastqsanger.gz | |||
| ERR10798716_1.fastq.gz | Fastqsanger.gz | |||
| ERR10798716_2.fastq.gz | Fastqsanger.gz |
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Project description:IntroductionSpondylarthritis (SpA) development in HLA-B27/human β2-microglobulin transgenic rat (B27-rat) is correlated with altered conventional dendritic cell (cDC) function that promotes an inflammatory pattern of CD4+T cells, including a biased expansion of pro-inflammatory Th17 population and imbalance of regulatory T cells cytokine profile. Transcriptomic analysis revealed that cDCs from B27-rats under express IL-27, an anti-inflammatory cytokine which induces the differentiation of IL-10+ regulatory T cells and inhibits Th17 cells.MethodsHere, we first investigated whether in vitro addition of exogenous IL-27 could reverse the inflammatory pattern observed in CD4+ T cells. Next, we performed preclinical assay using IL-27 to investigate whether in vivo treatment could prevent SpA development in B27-rats.Resultsin vitro addition of IL-27 to cocultures of cDCs and CD4+ T cell subsets from B27-rats reduced IL-17 and enhanced IL-10 production by T cells. Likewise, IL-27 inhibited the production of IL-17 by CD4+ T cells from SpA patients. Interestingly, in vivo treatment with recombinant IL-27 starting before SpA onset, inhibited SpA development in B27-rats through the suppression of IL-17/TNF producing CD4+ T cells.DiscussionOverall, our results reveal a potent inhibitory effect of IL-27 and highlight this cytokine as a promising new therapeutic target in SpA, especially for SpA patients non responders to currently approved biotherapies.
| S-EPMC9933703 | biostudies-literature
Project description:In the NOD mouse model of autoimmune diabetes, IL-27 stimulates CD4 and CD8 T cells to enhance their IFNγ production and diabetogenic capacity. Here, single-cell RNA sequencing and T cell adoptive transfer showed that IL-27 intrinsically controlled the differentiation of islet-infiltrating CD4 T cells by driving them toward an IL-21+ Th1 phenotype. Consequently, IL-27 signaling in CD4 T cells was important for BATF and granzyme B expression in islet CD8 T effectors. Complete absence of IL-21 signaling in CD8 T cells additionally impaired their cytokine production. BATF overexpression increased the diabetogenic potential of β-cell autoreactive CD8 T cells lacking help from CD4 T cell-derived IL-21. Macrophages were the main source of IL-27 in islets, whose expression correlated with T cell infiltration. IFNγ and CD40 signaling conferred by activated T cells induced macrophage IL-27 production. Collectively, our findings reveal a role of IL-27 in orchestrating interconnected positive feedback loops involving CD4 T cells, CD8 T cells, and macrophages in autoimmune diabetes.
2025-09-08 | GSE286747 | GEO
Project description:Interleukin 27 (IL-27) is a member of the IL-6 and/or IL-12 family that elicits both pro- and anti-inflammatory responses. Interferons (IFNs) are a family of cytokines that activate the JAK-STAT signaling pathway to induce an antiviral state in cells. Recent studies have reported that IL-27 also induces a robust antiviral response against diverse viruses, both in vitro and in vivo, suggest that IFNs and IL-27 share many similarities at the functional level. However, it is still unknown how similar or different IFN- and IL-27-dependent signaling pathways are. We reported that IFNs and IL-27 activate JAK-STAT signaling and induce shared pro-inflammatory and antiviral pathways in monocyte-derived macrophages (MDMs), leading to the common and unique expression of inflammatory factors and IFN-stimulated genes (ISGs). Importantly, the ability of IL-27 to induce those responses is independent of IFN induction and cellular lineage. Additionally, functional analysis demonstrated that like IFNs, IL-27-mediated response reduced chikungunya and dengue viruses replication in MDMs. In summary, IL-27 exhibits properties similar to those of all three types of human IFN, including the ability to stimulate a protective antiviral response.
2024-04-15 | GSE262963 | GEO
Project description:Interleukin (IL)-17A plays a central role in driving joint pathology in Spondyloarthritis (SpA). In this study, synovial tissues from patients with Axial SpA and Psoriatic arthritis were analyzed using single-cell RNA sequencing and spatial RNA profiling to pinpoint the cellular source of IL-17A. The results revealed that IL-17A expression is exclusively localized to CD4⁺CXCR6⁺ tissue resident memory Th17 (TRM17) cells, which interact with activated CLEC10A⁺ dendritic cells within the joint. These interactions coincide with an enhanced IL-17A response signature in both sublining and lining fibroblasts. Furthermore, in vitro-generated TRM17-like cells from blood memory CD4⁺ T cells recapitulated the in situ characteristics by producing IL-17A in response to T cell receptor stimulation, while IL-23 selectively amplified TCR-mediated IL-17F and IFN-γ production. Importantly, perturbation of the epigenetic regulator BRD1 impaired the generation of TRM17-like cells. These findings underscore the predominant role of TRM17 cells as the source of IL-17A in SpA and suggest that targeting BRD1 or depleting TRM17 cells may offer promising therapeutic strategies for achieving long-term disease remission.
2025-05-29 | GSE290921 | GEO
Project description:Interleukin (IL)-27 is a key immunosuppressive cytokine that counters T helper 17 (Th17) cell-mediated pathology. To identify mechanisms by which IL-27 might exert its immunosuppressive effect, we analyzed genes in T cells rapidly induced by IL-27. We found that IL-27 priming of naïve T cells upregulated expression of programmed death ligand 1 (PD-L1) in a signal transducer and activator of transcription (STAT)1-dependent manner. When co-cultured with naïve CD4+ T cells, IL-27-primed T cells inhibited the differentiation of Th17 cells in trans through a PD-1-PD-L1 interaction. In vivo, co-administration of naïve TCR transgenic T cells (2D2 T cells) with IL-27-primed T cells expressing PD-L1 inhibited the development of Th17 cells and protected from severe autoimmune encephalomyelitis. Thus, these data identify a suppressive activity of IL-27, by which CD4+ T cells can restrict differentiation of Th17 cells in trans.
2012-07-01 | GSE38375 | GEO
Project description:Background: IL-17A plays a role in the pathology of spondyloarthritis (SpA), as evidenced by the clinical efficacy of IL-17A inhibitors (IL-17Ai). Nevertheless, the exact role of IL-17A in driving synovial inflammation and pathological remodeling remains unknown. In this study, we investigated the molecular pathways affected by IL-17Ai in SpA synovitis to determine whether this response is tissue- and/or treatment-specific. Methods: Synovial biopsies from 12 peripheral SpA (pSpA) patients before and after 12 weeks of IL-17Ai treatment were analyzed by RNA-sequencing and qPCRs. The synovial tissue response to IL-17Ai in 7 psoriatic arthritis (PsA) patients was compared to: open-source gene expression data of skin biopsies from 15 psoriasis (PsO) patients treated with IL-17Ai; and synovial biopsies from 7 PsA patients receiving IL-12p40/IL-23p40 blockade. Results: Compared to baseline, IL-17Ai significantly modulated the expression of 1255 genes (549 upregulated and 706 downregulated, FDR < 0.1) in the synovium at week 12. The downregulated genes were predominantly associated with inflammatory processes and stromal functions. Comprehensive analysis revealed that IL-17Ai-mediated suppression of bone remodeling is independent of its inhibition of inflammatory pathways. While IL-17Ai consistently attenuated inflammation-related pathways in both psoriatic joints and skin, its effect on bone remodeling pathways was specific to the synovium. This distinguishes IL-17Ai from IL-12p40/IL-23p40 inhibitors, which, while mitigating synovial inflammation, did not affect tissue remodeling. Conclusions: Our findings provide new insights into the molecular mechanisms of IL-17A blockade in pSpA, underscoring its unique role in selectively targeting bone-remodeling processes specific to the joints of individuals with SpA.
2025-12-04 | GSE304063 | GEO
Project description:Interleukin (IL)-27 is a key immunosuppressive cytokine that counters T helper 17 (Th17) cell-mediated pathology. To identify mechanisms by which IL-27 might exert its immunosuppressive effect, we analyzed genes in T cells rapidly induced by IL-27. We found that IL-27 priming of naïve T cells upregulated expression of programmed death ligand 1 (PD-L1) in a signal transducer and activator of transcription (STAT)1-dependent manner. When co-cultured with naïve CD4+ T cells, IL-27-primed T cells inhibited the differentiation of Th17 cells in trans through a PD-1-PD-L1 interaction. In vivo, co-administration of naïve TCR transgenic T cells (2D2 T cells) with IL-27-primed T cells expressing PD-L1 inhibited the development of Th17 cells and protected from severe autoimmune encephalomyelitis. Thus, these data identify a suppressive activity of IL-27, by which CD4+ T cells can restrict differentiation of Th17 cells in trans. The roles of IL-6 and IL-27 in naïve CD4+ T cells was investigated by comparing global gene expression by Affymetrix Mouse Genome 430 2.0 Arrays. The functional outcome of STAT proteins was further evaluated by profiling gene expression changes between WT and STAT-deficient T cells in naïve CD4+ T cells with specific stimulation. All condition were done in biological triplicate.
2012-06-30 | E-GEOD-38375 | biostudies-arrayexpress
Project description:We aimed to elucidate the mechanism of IL-27/ IL-27 receptor signaling effects on S. aureus osteomyelitis via gene expression studies.
2021-03-16 | GSE168896 | GEO
Project description:Interleukin-27 (IL-27) has shown promise in halting tumor growth and mediating tumor regression in several models, including prostate cancer. We describe our findings on the effects of IL-27 on the gene expression changes of TC2R prostate adenocarcinoma cells. We utilized RNAseq to assess profile differences between empty vector control, vector delivering IL-27 modified at its C-terminus with a non-specific peptide, and IL-27 modified at the C-terminus with a peptide targeting the IL-6-Rα. The targeted IL-27 had higher bioactivity and activity in vivo in a recent study by our group, but the mechanisms underlying this effect had not been characterized in detail at the gene expression level on tumor cells. In the present work, we sought to examine potential mechanisms for targeted IL-27 enhanced activity directly on tumor cells. The targeted IL-27 appeared to modulate several changes that would be consistent with an anti-tumor effect, including upregulation in the Interferon (IFN) and Interferon regulatory factor (IRF), oxidative phosphorylation, Janus kinase/Signal transducers and activators of transcription (JAK/STAT), and eukaryotic initiation factor 2 (EIF2) signaling. Of these signaling changes predicted by ingenuity pathway analyses (IPA), the novel form also with the highest significance (-log(Benjamini–Hochberg (B-H))p-value) was the EIF2 signaling upregulation. We validated this predicted change by assaying for eukaryotic initiation factor 2 alpha (eIF2α), or phosphorylated eIF2α (p-eIF2α), and caspase-3 levels. We detected an increase in the phosphorylated form of eIF2α and in the cleaved caspase-3 fraction, indicating that the EIF2 signaling pathway was upregulated in these prostate tumor cells following targeted IL-27 gene delivery. This approach of targeting cytokines to enhance their activity against cancer cells is a novel approach to help augment IL-27′s bioactivity and efficacy against prostate tumors and could be extended to other conditions where it could help interfere with the EIF2α pathway and promote caspase-3 activation.
2024-08-28 | GSE248482 | GEO
Project description:Human newborns exhibit increased vulnerability and risk of mortality from infection. Increased susceptibility to infection during the neonatal period reflects key differences in the innate and adaptive immune responses relative to those in adult cells. We have previously shown an increase in the pleiotropic immune suppressive cytokine, IL-27, in macrophages derived from human umbilical cord blood compared with those obtained from adult peripheral blood. Similar findings exist in the neonatal murine system, as well as elevated splenic transcripts and serum levels. Recently, we established a murine model of neonatal sepsis to explore the impact of early life IL-27 levels on the host response to infection. In this model, neonatal mice deficient in IL-27 signaling exhibit reduced mortality, increased weight gain, and better control of the bacterial burden with reduced systemic inflammation. These results suggest that there is a reprogramming of the host response in the presence of IL-27 signaling. To explore this hypothesis, we profiled the neonatal transcriptome of the spleen in the presence or absence of Escherichia coli-induced sepsis in wild-type (WT) and IL-27Rα-deficient mice. The spleen, a known site of infection, exhibits increased IL-27 expression and bacterial burdens in WT pups that were significantly lower in IL-27Rα KO pups during infection. We identified 549 genes that were differentially expressed in WT neonates in response to E. coli infection. The upregulated genes were associated with inflammation, cytokine signaling, and G protein coupled receptor ligand binding and signaling. The expression level of these genes generally failed to increase in IL-27Rα KO mice upon the E. coli infection. We observed similar changes in gene expression, aligned with changes in chromatin accessibility, for macrophages isolated from the spleens of control and infected neonates with or without IL-27Rα KO, supporting macrophages as an innate myeloid population contributing to the inflammatory profile in septic WT pups. Collectively, our findings highlight a less inflammatory environment in KO pups that is not expected given the anti-inflammatory/suppressive activity of IL-27. However, it is consistent with a lower bacterial burden. This suggests that improved bacterial clearance in the absence of IL-27 signaling does not require a heightened inflammatory state, and instead, there is a direct relationship between IL-27 signaling and bacterial killing. An improved response to infection that is not reliant upon heightened levels of inflammation offers new promise to the potential of antagonizing IL-27 as a host-directed therapy for neonates without concern for driving inflammatory responses that are pathological to host tissues.
2023-02-07 | GSE220049 | GEO