Gene Expression Analysis in Peripheral Blood of Patients with Rheumatoid Arthritis
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE12653 | GEO | 2009/09/03
SECONDARY ACCESSION(S): PRJNA113057
REPOSITORIES: GEO
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Project description:Peripheral blood cells in patients with rheumatoid arthritis before/after IL-6 inhibition The obtained conclusions on the change of each gene expression level before and after MRA medication were as follows. (1) In the case of IL-6, the specific time profile that the expression level dropped at day 21 and increased to some extent at day 42 was observed in 2 of 18 subjects. In other subjects, quite small change or small increase after day 7 was observed. (2) In the case of IL-6R as well as in IL-6, the specific time profile that the expression level dropped at day 21 and increased to some extent at day 42 was observed in 1 of 18 subjects. In other subjects, slow and small increase was observed in 6 of 18. (3) The ratio of mRNA expression level of membrane and soluble type of IL-6R showed marginal difference after tocilizumab treatment, (4) The distinct change of expression level of cytochrome P450 mRNA after tocilizumab treatment was hardly observed in most patients. The measurement of expression level of several genes shown below in peripheral blood of human subjects (18 patients with rheumatic disease) before and after tocilizumab medication using DNA microarray (Hitachi human oligo chip) was conducted in this test, 1) Interleukin 6 (IL-6), membrane IL-6 receptor (IL-6R) and soluble type of the IL-6R, 2) several cytochrome P450 as follows: CYP3A4, CYP2D6, CYP2C9, CYP2C19. Number of human subjects was 18 and peripheral blood samples drawn at 4 time points: day 0 (the first Omeprazole administration was done), day 7 (Tocilizumab administration was done), day 21 and day 42 for each subject were analyzed. On day 0 and day 7, the blood sampling was done before drug administration.
2010-06-24 | E-GEOD-12653 | biostudies-arrayexpress
Project description:Interleukin-27 (IL-27) can partially reduce tumor growth in several animal models, including pros-tate cancer. We describe our findings on the effects of IL-27 gene delivery on prostate cancer cells and how sequential therapy with IL-18 enhances the efficacy of IL-27. We applied IL-27 and IL-18 deliv-ery with the goal of reducing prostate tumor growth, first in cell culture and then in an immunocom-petent mouse model. The combination of IL-27 followed by IL-18 (2718) successfully reduced can-cer cell viability, with significant effects found for a particular combination sequence. Interestingly, when we compared the 2718 combination with a single cytokine targeted to IL-6R via an oligo-peptide (27pepL) recently developed by our group, we observed similar efficacy. This efficacy was further enhanced when 27pepL was sequenced with IL-18 (27pepL18)
2021-07-27 | GSE178142 | 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:Endothelial function and integrity are compromised after allogeneic bone marrow transplantation (BMT) but how this affects immune responses broadly remains unknown. Using a preclinical model of cytomegalovirus (CMV) reactivation after BMT, we found compromised antiviral humoral responses induced by IL-6 signaling. IL-6 signaling in T cells maintained Th1 cells resulting in sustained IFN secretion which promoted endothelial cell (EC) injury, loss of the neonatal Fc receptor (FcRn) responsible for immunoglobulin G (IgG) recycling, and rapid IgG loss. In contrast, recipient IgG producing cells are rapidly eliminated after BMT. T cell-specific deletion of IL-6R led to persistence of recipient-derived CMV-specific IgG and inhibited CMV reactivation. Deletion of IFN in donor T cells also eliminated EC injury and FcRn loss. In a phase III clinical trial, blockade of IL-6R with tocilizumab promoted CMV-specific IgG persistence and significantly attenuated early HCMV reactivation. In sum, IL-6 invokes IFN-dependent EC injury and consequent IgG loss leading to CMV reactivation. Hence, cytokine inhibition represents a logical strategy to prevent endothelial injury thereby preserving humoral immunity after immunotherapy.
2024-04-01 | GSE252180 | GEO
Project description:COVID-19 has posed a significant threat to global health. Early data has revealed that IL-6, a key regulatory cytokine, plays an important role in the cytokine storm of COVID-19. Multiple trials are therefore looking at the effects of Tocilizumab, an IL-6 receptor antibody that inhibits IL-6 activity, on treatment of COVID-19, with promising findings. As part of a clinical trial looking at the effects of Tocilizumab treatment on kidney transplant recipients with subclinical rejection, we performed single-cell RNA sequencing of comparing stimulated PBMCs before and after Tocilizumab treatment. We leveraged this data to create an in vitro cytokine storm model, to better understand the effects of Tocilizumab in the presence of inflammation. Tocilizumab-treated cells had reduced expression of inflammatory-mediated genes and biologic pathways, particularly amongst monocytes. These results support the hypothesis that Tocilizumab may hinder the cytokine storm of COVID-19, through a demonstration of biologic impact at the single-cell level.
2020-12-11 | GSE163014 | GEO
Project description:BACKGROUND - IL-6 mediates graft-versus-host disease (GVHD) in experimental allogeneic stem cell transplantation (alloSCT) and is an attractive therapeutic target. METHODS - A registered phase I/II study (ACTRN12612000726853) of IL-6 receptor (IL-6R) neutralizing antibody administration on day -1 to patients receiving full or reduced-intensity conditioning (RIC) and alloSCT from HLA-matched sibling or unrelated donors with standard cyclosporin and methotrexate GVHD prophylaxis. The primary endpoint was incidence of grade II-IV acute GVHD. Outcomes were compared to a non-randomized but contemporaneous group of study patients receiving the same alloSCT in the absence of IL-6R mAb. FINDINGS - Cytokine and pharmacokinetic analysis confirmed transient IL-6 dysregulation in the first month after alloSCT with complete inhibition following IL-6R mAb administration. With median follow up of 497 days, the incidence of grade II-IV GVHD was 12.5% in recipients of IL-6R inhibition (n = 48) versus 41.5% in the (n = 53) control cohort (P = 0.001). Low rates of acute GVHD were noted in patients receiving IL-6R inhibition relative to control patients following both myeloablative (12.5% vs. 46.4%, P = 0.03) and RIC (12.5% vs. 36.0%, P = 0.04). The incidence of severe (grade III/IV) acute GVHD was 4.2% in recipients of IL-6R inhibition versus 20.8% in the control cohort (P = 0.012). Relapse and chronic GVHD were unchanged. Immune reconstitution was preserved in recipients of IL-6R inhibition, but qualitatively modified with suppression of known pathogenic STAT3-dependent pathways. INTERPRETATION - IL-6 is the principal detectable and dysregulated cytokine secreted after alloSCT and its inhibition is a potential new and simple strategy to protect from acute GVHD despite robust immune reconstitution and a sustained graft-versus-leukemia effect. Single colour, Illumina Human HT12v4 Beadarrays.
2014-09-09 | E-GEOD-61201 | biostudies-arrayexpress
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: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.
2014-08-06 | BIOMD0000000537 | BioModels
Project description:Dwivedi2014 - Healthy Volunteer IL6
Model
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 Healthy Volunteer model are 2c and
2d.
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:
BIOMD0000000534.
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.
2014-08-05 | BIOMD0000000534 | BioModels
Project description:Dwivedi2014 - Crohns IL6 Disease model -
sgp130 activity
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.
The figure referring to this Crohn's Disease model is 6b.
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:
BIOMD0000000536.
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.
2014-08-06 | BIOMD0000000536 | BioModels