IL-12 and IL-23 dependent gene induction in purified CD19+, CD8+, CD4+, gdTCR+ and CD56+ cells
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE120843 | GEO | 2018/10/25
REPOSITORIES: GEO
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Project description:IL-12 and IL-23 dependent gene induction in purified CD19+, CD8+, CD4+, gdTCR+ and CD56+ cells
| PRJNA494701 | ENA
Project description:IL-23 and IL-12, two structurally related heterodimeric cytokines sharing a common subunit, divergently promote Th cell development and expansion. Both cytokines have been implicated in the pathogenesis of thyroid-associated ophthalmopathy (TAO), an autoimmune component of Graves disease. In TAO, CD34+ fibrocytes, putatively derived from bone marrow, can be identified in the orbit. There they masquerade as CD34+ orbital fibroblasts (OF) (CD34+ OF) and cohabitate with CD34- OF in a mixed fibroblast population (GD-OF). Slit2, a neural axon repellent, is expressed and released by CD34- OF and dampens the inflammatory phenotype of fibrocytes and CD34+ OF. In this study we report that thyrotropin (TSH) and the pathogenic, GD-specific monoclonal autoantibody, M22, robustly induce IL-23 in human fibrocytes; however, IL-12 expression is essentially undetectable in these cells under basal conditions or following TSH-stimulation. In contrast, IL-12 is considerably more inducible in GD-OF, cells failing to express IL-23. This divergent expression and induction of cytokines appears to result from cell type-specific regulation of both gene transcription and mRNA stabilities. It appears that the JNK pathway activity divergently attenuates IL-23p19 expression while enhancing that of IL-12p35. The shift from IL-23p19 expression in fibrocytes to that of IL-12p35 in their derivative CD34+ OF results from the actions of Slit2. Thus, Slit2 might represent a molecular determinant of balance between IL-23 and IL-12 expression, potentially governing immune responses in TAO.
| S-EPMC7365299 | biostudies-literature
Project description:Interleukin 23 (IL-23) triggers pathogenic features in pro-inflammatory, IL-17-secreting T cells (Th17 and Tγδ17) that play a key role in the development of inflammatory diseases. However, the IL-23 signaling cascade remains largely undefined. Here we used quantitative phosphoproteomics to characterize IL-23 signaling in primary murine Th17 cells. We quantified 6,888 phosphorylation sites in Th17 cells, and found 168 phosphorylations regulated upom IL-23 stimulation. IL-23 increased the phosphorylation of the myosin regulatory light chain (RLC), an actomyosin contractibility marker, in Th17 and Tγδ cells. IL-23-induced RLC phosphorylation required JAK2 and ROCK catalytic activity, and the study of the IL-23/ROCK axis revealed an unexpected role of IL-23 in the migration of Tγδ17 and Th17 cells. Moreover, pharmacological inhibition of ROCK reduced Tγδ17 recruitment to inflamed skin upon challenge with inflammatory agent Imiquimod. This work: i) provides new insights into phosphorylation networks that control Th17 cells, ii) widely expands the current knowledge on IL-23 signaling, and iii) contributes to the increasing list of immune cells subsets characterized by global phosphoproteomic approaches.
2020-03-25 | PXD016633 | Pride
Project description:Pyoderma Gangrenosum (PG) is a rare and extremely painful neutrophilic dermatosis associated with non-healing cutaneous ulcers affecting 3-10 individuals per million people. The etiology and molecular pathogenetic events of this disease are yet unknown. To investigate how this therapeutic regime shaped the underlying inflammatory response, we performed spatial transcriptomics on lesional biopsies from patients before and after ustekinumab treatment. Our study provides high resolution temporal insights into the inflammatory environment of PG lesional skin following treatment with IL-12/IL-23 blockade in two patients with classic and peristomal PG. This work highlights that while inhibition of representative cytokines of the Th1 and Th17 pathways shows promise as a treatment for PG patients, it does not dampen all active inflammatory pathways.
2024-08-28 | GSE274489 | GEO
Project description:Chimeric antigen receptor (CAR) T cell therapy represents a significant advancement in cancer therapy. Larger studies have shown ∼90% complete remission rates against chemoresistant and/or refractory CD19+ leukemia or lymphoma. Effective CAR T cell therapy is highly dependent on lymphodepleting preconditioning, which is achieved through chemotherapy or radiotherapy that carries with it significant toxicities. These can exclude patients of low performance status. In order to overcome the need for preconditioning, we constructed fully mouse first and second generation anti-murine CD19 CARs with or without interleukin-12 (IL-12) secretion. To test these CARs, we established a mouse model to reflect the human situation without preconditioning. Murine second generation CAR T cells expressing IL-12 were capable of eradicating established B cell lymphoma with a long-term survival rate of ∼25%. We believe this to be the first study in a truly lymphoreplete model. We provide evidence that IL-12-expressing CAR T cells not only directly kill target CD19+ cells, but also recruit host immune cells to an anti-cancer immune response. This finding is critical because lymphodepletion regimens required for the success of current CAR T cell technology eliminate host immune cells whose anti-cancer activity could otherwise be harnessed by strategies such as IL-12-secreting CAR T cells.
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Project description:The autoantigen in Goodpasture disease is the noncollagenous domain of alpha3 type IV collagen [alpha3(IV)NC1]. We previously demonstrated that IL-12p40(-/-) mice are protected from experimental autoimmune anti-glomerular basement membrane (anti-GBM) glomerulonephritis, seemingly defining a role for IL-12 in this disease; however, the recent identification of IL-23, a heterodimer composed of IL-12p40 and IL-23p19 subunits, raises the possibility that IL-23, rather than IL-12, may modulate this disease instead. We immunized wild-type, IL-12p35(-/-) (IL-12 deficient, IL-23 intact), IL-12p40(-/-) (deficient in both IL-12 and IL-23), and IL-23p19(-/-) (IL-12 intact, IL-23 deficient) mice with recombinant mouse alpha3(IV)NC1. Wild-type mice developed autoreactivity to alpha3(IV)NC1: Humoral responses, cellular responses, renal histologic abnormalities, leukocyte accumulation, autoantibody deposition, and IL-17A mRNA expression (a cytokine produced by the IL-23-maintained Th17 subset). IL-23 but not IL-12 was detected in the immune system. Regardless of the presence of IL-12, mice deficient in IL-23 were protected, but mice with IL-23 were not. Both IL-23-deficient strains exhibited lower autoantibody titers, reduced cellular reactivity, diminished cytokine production (IFN-gamma [Th1], IL-17A [Th17], TNF, and monocyte chemoattractant protein 1), and less renal disease and glomerular IgG deposition. The deficient responses in the absence of IL-23 were not due to increased regulatory T cells; IL-12p40(-/-) and IL-23p19(-/-) mice did not show increased proportions of CD4(+)CD25(+)FoxP3(+) cells or IL-10 levels early in the immune response. In conclusion, autoreactivity to the Goodpasture antigen is directed primarily by IL-23, absence of which results in hyporeactivity including but extending beyond a deficient Th17 response.
| S-EPMC2678043 | biostudies-literature
Project description:Impact statementOur article is focused on emerging pathogenetic pathways in systemic lupus erythematosus (SLE). Notably, IL-12 and IL-23 have been described as emerging cytokines in SLE pathogenesis. We know that IL-23 stimulates Th17 cells to produce IL-17. We try to point out the importance of IL-23/Th17 axis in SLE and to focus on the interaction between this axis and IL-12. Ustekinumab, a fully human IgG1κ monoclonal antibody directed towards the p40 shared subunit of IL-12 and IL-23, has been recently investigated in SLE, suggesting a potential novel therapeutic strategy in SLE. To our knowledge, there are no reviews which simultaneously focus on IL-12 an IL-23/Th17 axis in SLE. Thus, we believe our work will be of interest to the readers.
| S-EPMC6362534 | biostudies-literature
Project description:We stimulated T-cell blasts from IL23R R381Q homozygotes (n = 2), healthy controls homozygous for the ancestral allele (n = 9), homozygous individuals for TYK2 P1104A (n = 2) that selectively impairs responses to IL-23, and one patient each with autosomal recessive, complete TYK2 or IL-12Rb1 deficiency with IL-12, IL-23, IL-1b, and IL-1b plus IL-23 for 6 hours and performed RNA-sequencing. We used IL-1b as an IL-23-sensitizing agent as previously reported. We found that while T-cell blasts from IL23R R381Q homozygotes respond normally to IL-12 and IL-1b, their response to IL-23 and to IL-23 plus IL-1b is impaired
2023-01-13 | GSE216458 | GEO
Project description:Interleukin (IL)-1 family cytokines are essential for host defense at epithelial barriers. The IL-1 family member IL-33 was recently linked to stress granules (SGs). Formation of SGs and other biomolecular condensates is promoted by proteins containing low complexity regions (LCRs). Computational analysis predicted LCRs in six of the eleven IL-1 family members. Among these, IL-38 contained a long LCR including two amyloid cores. IL-38 localized to intracellular condensates in keratinocytes exposed to oxidative stress (OS) and formed OS-induced amyloid aggregates in cells and in vitro. Top-down proteomic analysis was performed on purified recombinant IL-38 protein to characterize the presence of possible disulfide bonds.
2024-11-03 | PXD052918 | Pride
Project description:We performed a PCR array of 84 ECM-related genes using RNA obtained from dermal fibroblasts stimulated presence or absence of IL-12, IL-23 or IL-27. The effects of IL-12, -23 or -27 on COL1A2 mRNA expression were less than 2-fold, as compared with untreated cells.
2016-03-03 | GSE78838 | GEO