Expression profile of shMCT-1 in 4T1 metastatic murine triple-negative breast cancer (TNBC) cell lines in response to anti-IL6R immunotherapy
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE237506 | GEO | 2024/03/21
REPOSITORIES: GEO
Similar Datasets
Project description:In Interleukin (IL)-6 signalling, IL-6 site I binds to the IL-6 receptor (IL-6R) first, following by IL-6 site II interaction to domain 2/3 of gp130 to form premature trimeric IL-6:IL‑6R:gp130 receptor complexes. Formation of the mature hexameric receptor complex is then facilitated by the inter-trimeric interaction of IL-6 site III with domain 1 of the opposing gp130. The two gp130-associated Janus kinases (JAKs) trans-phosphorylate when their spatiotemporal pairing is correct, which causes the activation of STAT, ERK, and AKT pathways in a balanced manner. Since the intracellular domain (ICD) of IL-6R is not needed for STAT/ERK/AKT phosphorylation, we investigated the conditions under which a chimeric IL-6RECD-gp130TMD/ICD receptor protein confers biological activity. For IL‑6RECD‑gp130TMD/ICD, the extracellular domain (ECD) of IL-6R was fused to the transmembrane domain (TMD) and ICD of gp130. Co-expression of IL‑6RECD‑gp130TMD/ICD with signalling-deficient gp130 variants did not induce IL-6 signalling, suggesting that the assembly of hexameric complexes failed to dimerize the IL-6R-associated JAKs correctly. By mimicking the premature trimeric receptor complex, IL-6-mediated dimerization of IL-6RECD-gp130TMD/ICD with the single-cytokine-binding variant gp130DD1 induced signalling. Of note, IL-6 signalling via these synthetic gp130DD1:IL-6RECD-gp130TMD/ICD complexes resulted predominantly in STAT3 phosphorylation. A STAT3-dominated profile was also observed after IL-6-induced signalling mediated by a JAK-deficient IL‑6RECD‑gp130TMD/ICDDJAK variant in complex with the JAK-proficient but STAT/ERK/AKT-deficient gp130JAKDICD variant. Our data showed that effective ERK/AKT signalling could not be executed after intracellular domain swapping from gp130 to the IL-6R. Taken together, the chimeric IL-6R/gp130 receptor may be helpful in the creation of customized synthetic IL-6 signalling.
2024-05-17 | GSE267270 | GEO
Project description:Interleukin-6 (IL-6) plays an important role in progressive bone loss in rheumatoid arthritis (RA). However, the molecular mechanisms through which IL-6 propels RA synovial fibroblasts (RASFs) to contribute to bone loss are not fully understood. In the present study, we investigated the effects of IL-6 and IL-6 receptor (IL-6/IL-6R induced trans-signaling in human RASFs. Treatment of human RASFs with IL-6 and IL-6 receptor (IL-6/IL-6R, 100 ng/ml each) alone or in combination with M-CSF (2 ng/ml) and RANKL (10 ng/ml) for 12 days resulted in the phenotypic changes to osteoclast-like features as determined by increase in TRAP staining and enhanced pit formation by ~3-fold in bone resorption assay in vitro. IL-6/IL-6R induced a dose-dependent increase in the expression of transcription factor Ets2 and enhanced its nuclear translocation in human RASFs. Interestingly, the untargeted proteomics analysis of the conditioned media from IL6/IL6R activated RASFs using Mass-Spectrometry (MS) technique and Trans-Proteomic Pipeline tool showed the production of 113 analytes unique to IL-6/IL-6R stimulation. Further analysis of the proteomics data using STRING database for pathway analysis showed the impact of IL-6/IL-6R on immunometabolic reprogramming of human RASFs towards osteoclast-like phenotype, which was partly mediated through Ets2. These preliminary studies identified a novel role of IL-6/IL-6R-mediated trans signaling in the metabolic reprogramming in RASFs that could potentially be targeted by inhibiting Ets2 to limit their role in bone resorption in RA.
2021-11-02 | PXD028374 | Pride
Project description:Dwivedi2014 - Crohns IL6 Disease model -
Anti-IL6R Antibody
This model is comprised of four models:
[BIOMD0000000534]
Healthy Volunteer model
[BIOMD0000000535]
Crohn's Disease - IL-6 Antibody
[BIOMD0000000536]
Crohn's Disease - sgp130FC
[BIOMD0000000537]
Crohn's Disease - IL-6Ra Antibody
Possible avenues for Interleukin-6 (IL-6) inhibition in
treating Crohn's disease are compared here. Each model refers to
separate ligands. The system simulates differential activity of the
ligands on the signalling of IL-6.
This affects Signal Transducer and Activator of
Transcription 3 (STAT3) activity on the production of
biomarker C-Reactive Protein (CRP) expression.
Figures referring to this Crohn's Disease model are 3a, 4d,
4e, 4f and 5b.
This model is described in the article:
A multiscale model of
interleukin-6-mediated immune regulation in Crohn's disease and
its application in drug discovery and development.
Dwivedi G, Fitz L, Hegen M, Martin
SW, Harrold J, Heatherington A, Li C.
CPT Pharmacometrics Syst Pharmacol
2014; 3: e89
Abstract:
In this study, we have developed a multiscale systems model
of interleukin (IL)-6-mediated immune regulation in Crohn's
disease, by integrating intracellular signaling with
organ-level dynamics of pharmacological markers underlying the
disease. This model was linked to a general pharmacokinetic
model for therapeutic monoclonal antibodies and used to
comparatively study various biotherapeutic strategies targeting
IL-6-mediated signaling in Crohn's disease. Our work
illustrates techniques to develop mechanistic models of disease
biology to study drug-system interaction. Despite a sparse
training data set, predictions of the model were qualitatively
validated by clinical biomarker data from a pilot trial with
tocilizumab. Model-based analysis suggests that strategies
targeting IL-6, IL-6R?, or the IL-6/sIL-6R? complex are less
effective at suppressing pharmacological markers of Crohn's
than dual targeting the IL-6/sIL-6R? complex in addition to
IL-6 or IL-6R?. The potential value of multiscale system
pharmacology modeling in drug discovery and development is also
discussed.CPT: Pharmacometrics & Systems Pharmacology
(2014) 3, e89; doi:10.1038/psp.2013.64; advance online
publication 8 January 2014.
This model is hosted on
BioModels Database
and identified by:
BIOMD0000000537.
To cite BioModels Database, please use:
BioModels Database:
An enhanced, curated and annotated resource for published
quantitative kinetic models.
To the extent possible under law, all copyright and related or
neighbouring rights to this encoded model have been dedicated to
the public domain worldwide. Please refer to
CC0
Public Domain Dedication for more information.
2024-09-02 | BIOMD0000000537 | BioModels
Project description:All except one cytokine of the Interleukin (IL-)6 family share glycoprotein (gp) 130 as the common b receptor chain. Whereas Interleukin (IL-)11 signal via the non-signaling IL-11 receptor (IL-11R) and gp130 homodimers, leukemia inhibitory factor (LIF) recruits gp130:LIF receptor (LIFR) heterodimers. Using IL-11 as a framework, we exchange the gp130 binding site III of IL-11 with the LIFR binding site III of LIF. The resulting synthetic cytokimera GIL-11 efficiently recruits the non-natural receptor signaling complex consisting of gp130, IL-11R and LIFR resulting in signal transduction and proliferation of factor-depending Ba/F3 cells. Besides LIF and IL-11, GIL-11 does not activate receptor complexes consisting of gp130:LIFR or gp130:IL-11R, respectively. Human GIL-11 shows cross-reactivity to mouse and rescued IL-6R deficient mice following partial hepatectomy, demonstrating gp130:IL-11R:LIFR signaling efficiently induced liver regeneration. With the development of the cytokimera GIL-11, we devise the functional assembly of the non-natural cytokine receptor complex of gp130:IL-11R:LIFR.
2023-04-19 | GSE226064 | GEO
Project description:The pro-inflammatory cytokine IL-6 is elevated in both blood and airways in asthma. IL-6 signaling is regulated by its receptor composed of two proteins, IL-6R and GP130, that are found in both membrane and soluble forms. The interaction of IL-6 with soluble IL-6R (sIL-6R) can trigger IL-6 trans-signaling in cells such as epithelial cells and fibroblasts, which express GP130, but do not produce sufficient IL-6R. We aimed to analyze IL-6 trans-signaling in the airways after an allergen challenge and to examine the potential source of sIL-6R and sGP130. In addition to protein analysis of bronchoalveolar lavages by ELISA and flow cytometry, we performed next-generation RNA sequencing (RNA-seq) to study the expression of the IL-6R subunits by eosinophils activated by IL-3 in vitro. RNA-seq and proteomic analyses confirmed that eosinophils do not produce GP130 but produce both IL-6R and ADAM10, a metalloproteinase that cleaves membrane IL-6R into sIL-6R.
2020-10-22 | GSE159782 | GEO
Project description:To determine the phenotypic differences in blood cells that are regulated by the IL-6R
2019-06-19 | E-MTAB-8034 | biostudies-arrayexpress
Project description:Background A large unmet therapeutic need exists in inflammatory bowel diseases (IBD). Inhibition of interleukin (IL)-6 appears to be effective, but the therapeutic benefit of a complete IL-6/IL-6R blockade is limited by profound immunosuppression. Evidence has emerged, that chronic pro-inflammatory activity of IL-6 is mainly mediated by trans-signalling via a complex of IL-6 bound to soluble IL-6R engaging the gp130 receptor without the need of membrane bound IL6R. We have developed a decoy protein, sgp130Fc, which exclusively blocks IL-6 pro-inflammatory trans-signalling and has shown efficacy in preclinical models of IBD, without signs of immunosuppression. Methods We present a 12-week, open label, prospective phase IIa trial (FUTURE) in 16 patients with active IBD treated with the trans-signalling inhibitor olamkicept (sgp130Fc) to assess molecular mechanisms, safety and effectiveness of IL-6 trans-signalling blockade in vivo. We performed in-depth molecular profiling at various time points before and after therapy induction to identify the mechanism of action of olamkicept. Results Olamkicept was well tolerated and induced clinical response in 44% and clinical remission in 19% of patients. Clinical effectiveness coincided with target inhibition (reduction of phosphorylated STAT3) and marked transcriptional changes in the inflamed mucosa. An olamkicept-specific transcriptional signature, distinguishable from remission signatures of anti-TNF (infliximab) or anti-integrin (vedolizumab) therapies was identified. Conclusion Our data suggest that blockade of IL-6 trans-signaling holds large promise for the therapy of IBD and should undergo full clinical development as a new immunoregulatory therapy of IBD.
2021-04-10 | GSE171770 | GEO
Project description:MCT-1 (malignant T cell amplified sequence) is an oncoprotein encoded by Mcts1 gene that regulates translation re-initiation, ribosomal recycling, and tumorigenicity. We have characterized the metastasis cascade, immune evasion,and inflammatory responses which are suppressed by silencing of MCT-1 (shMCT-1) through transcriptional profiling of the 4T1 metastatic TNBC cell line. shMCT-1-altered gene lists are related to the IFNα-response, IFNγ-response, IL-6/JAK/STAT pathway, inflammatory response. shMCT-1 also suppresses expression of upstream regulators of PD-L1 and epidermal growth factor receptor (EGFR) ligands as compared to scramble cells.
2022-06-25 | GSE206910 | GEO
Project description:This study examines the transcriptional changes invoked by activation of gp130 signaling in different mouse models of B cell lymphomagenesis. In order to study the in vivo effects of aberrant activity of IL-6/IL-6R/gp130-JAK/STAT3 signaling, we designed a transgene that allows conditional expression of L-gp130 by generating a ROSA26 knock-in mouse strain where compound L-gp130 and ZsGreen expression from the CAG promoter is prevented by a loxP- and a rox-flanked stop cassette. Total RNA extracted from purified B cells from young CD19Cre+/- ;L-gp130fl/+ and wildtype control mice was sequenced using unique molecular identifiers (UMI) in a paired end design where read1 corresponds to the cDNA and read2 contains the UMI. Furthermore, aging CD19Cre+/- ;L-gp130fl/+ animals developed tumors located predominantly in mesenteric lymph nodes. Infiltration of CD19;L-gp activated B cells was determined by Flow Cytometry and ZsGreen expression. Total RNA from tumors generally containing >60% ZsGreen+ cells was profiled as described above, for tumors with lower CD19;L-gp activated B cell content FACS was applied. In order to study the effects of activated IL-6/IL-6R/gp130-JAK/STAT3 signaling on Eµ-Myc-driven lymphomagenesis, CD19Cre;L-gp130fl;Eµ-Myc triple transgenic mice were generated and fetal liver hematopoietic stem/progenitor cell (FL-HSPC) grafts were transplanted into lethally irradiated syngeneic mice alongside FL-HSPC from CD19Cre;L-gp130f and Eµ-Myc control mice. Lastly, IL-6/IL-6R/gp130-JAK/STAT3 signaling was activated in the entire hematopoetic system using Vav1Cre resulting in Vav1Cre+/- ;L-gp130fl/+ animals. Independent of the time point of activation during hematopoietic and B cell differentiation, all Cre;L-gp compound mice succumbed to tumors of B cell origin.
2019-06-06 | GSE132148 | GEO
Project description:Protection against endothelial damage is recognized as a frontline approach to preventing the progression of cytokine release syndrome (CRS). Accumulating evidence has demonstrated that interleukin-6 (IL-6) promotes vascular endothelial damage during CRS, although the molecular mechanisms remain to be fully elucidated. Targeting IL-6 receptor signaling delays CRS progression; however, current options are limited by persistent inhibition of the immune system. Here, we show that endothelial IL-6 trans-signaling promoted vascular damage and inflammatory responses via hypoxia-inducible factor-1α (HIF1α)‒induced glycolysis. Using pharmacological inhibitors targeting HIF1α activity or mice with the genetic ablation of gp130 in the endothelium, we found that inhibition of IL-6R‒HIF1α signaling in endothelial cells protected against vascular injury caused by septic damage and provided survival benefit in a mouse model of sepsis. In addition, we developed a short half-life anti-IL-6R antibody (silent anti-IL-6R antibody) and found that it was highly effective at augmenting survival for sepsis and severe burn by strengthening the endothelial glycocalyx and reducing cytokine storm, and vascular leakage. Together, our data advance the role of endothelial IL-6 trans-signaling in the progression of CRS and indicate a potential therapeutic approach for burns to address the lack of burn-specific treatments.
2023-12-18 | GSE241139 | GEO