Nature-inspired IL-1 targeted therapy to treat chronic inflammatory diseases
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE305182 | GEO | 2025/10/31
REPOSITORIES: GEO
Similar Datasets
Project description:Baker2013 - Cytokine Mediated Inflammation in
Rheumatoid Arthritis
This model by Baker M. 2013, describes
the interaction between pro and anti-inflammatory cytokine
signalling in rheumatoid arthritis.
Using two ordinary differential equations, the first model
[BIOMD0000000550]
analyses bifurcation and describes different pathological states by
altering inflammatory regulation parameters.
The second model
[BIOMD0000000549]
includes the effect that ageing has on pro-inflammatory signalling,
allowing for time-dependant properties and disease progression to
be observed. The author also describes potential dosing for
reversal of the disease state.
This model is described in the article:
Mathematical modelling of
cytokine-mediated inflammation in rheumatoid arthritis.
Baker M, Denman-Johnson S, Brook BS,
Gaywood I, Owen MR.
Math Med Biol 2013 Dec; 30(4):
311-337
Abstract:
Rheumatoid arthritis (RA) is a chronic inflammatory disease
preferentially affecting the joints and leading, if untreated,
to progressive joint damage and disability. Cytokines, a group
of small inducible proteins, which act as intercellular
messengers, are key regulators of the inflammation that
characterizes RA. They can be classified into pro-inflammatory
and anti-inflammatory groups. Numerous cytokines have been
implicated in the regulation of RA with complex up and down
regulatory interactions. This paper considers a two-variable
model for the interactions between pro-inflammatory and
anti-inflammatory cytokines, and demonstrates that mathematical
modelling may be used to investigate the involvement of
cytokines in the disease process. The model displays a range of
possible behaviours, such as bistability and oscillations,
which are strongly reminiscent of the behaviour of RA e.g.
genetic susceptibility and remitting-relapsing disease. We also
show that the dose regimen as well as the dose level are
important factors in RA treatments.
This model is hosted on
BioModels Database
and identified by:
BIOMD0000000550.
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 | BIOMD0000000550 | BioModels
Project description:Baker2013 - Cytokine Mediated Inflammation in
Rheumatoid Arthritis - Age Dependant
This model by Baker M. 2013, describes
the interaction between pro and anti-inflammatory cytokine
signalling in rheumatoid arthritis.
Using two ordinary differential equations, the first model
[BIOMD0000000550]
analyses bifurcation and describes different pathological states by
altering inflammatory regulation parameters.
The second model
[BIOMD0000000549]
includes the effect that ageing has on pro-inflammatory signalling,
allowing for time-dependant properties and disease progression to
be observed. The author also describes potential dosing for
reversal of the disease state.
This model is described in the article:
Mathematical modelling of
cytokine-mediated inflammation in rheumatoid arthritis.
Baker M, Denman-Johnson S, Brook BS,
Gaywood I, Owen MR.
Math Med Biol 2013 Dec; 30(4):
311-337
Abstract:
Rheumatoid arthritis (RA) is a chronic inflammatory disease
preferentially affecting the joints and leading, if untreated,
to progressive joint damage and disability. Cytokines, a group
of small inducible proteins, which act as intercellular
messengers, are key regulators of the inflammation that
characterizes RA. They can be classified into pro-inflammatory
and anti-inflammatory groups. Numerous cytokines have been
implicated in the regulation of RA with complex up and down
regulatory interactions. This paper considers a two-variable
model for the interactions between pro-inflammatory and
anti-inflammatory cytokines, and demonstrates that mathematical
modelling may be used to investigate the involvement of
cytokines in the disease process. The model displays a range of
possible behaviours, such as bistability and oscillations,
which are strongly reminiscent of the behaviour of RA e.g.
genetic susceptibility and remitting-relapsing disease. We also
show that the dose regimen as well as the dose level are
important factors in RA treatments.
This model is hosted on
BioModels Database
and identified by:
BIOMD0000000549.
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 | BIOMD0000000549 | BioModels
Project description:Through gene expression profiling in cultured lymphocytes and PBMCs from a large set of T1D patients and controls, we demonstrate that IL-1ra may protect against the development of islet autoimmunity and T1D through down-regulating a large number of inflammatory genes and pathways. Keywords: autoimmunity; IL-1Ra;Type 1 diabetes (T1D) To elucidate the molecular mechanism underlying the action of IL-1ra, we profiled gene expression in peripheral blood mononuclear cells (PBMC) cultured with sera from low or high IL-1ra subjects. To avoid potential heterogeneity in responder cells from different subjects, PBMCs from one healthy donor were cultured for six hours with 20% of sera from six subjects with low IL-1ra and six subjects with high IL-1ra. Gene expression in the cultured cells was analyzed with the Illumina HumanRef-8 v3.0 beadchips
2012-12-01 | E-GEOD-14368 | biostudies-arrayexpress
Project description:The hallmark of Kaposi’s sarcoma (KS), the most common cancer in HIV-infected patients caused by Kaposi’s sarcoma-associated herpesvirus (KSHV) infection, is hyperinflammation. However, the role of inflammation and the mechanism of induction of inflammation in KSHV-induced cancer remain unclear. In a previous high-throughput screening against KSHV-induced oncogenesis, over half of the identified candidates were anti-inflammatory agents. Among them, dexamethasone, a common anti-inflammatory corticosteroid, functions through binding to and activating glucocorticoid receptor (GR). In this study, we examined the mechanism mediating KSHV-induced inflammation. We found that numerous inflammatory pathways were activated in KSHV-transformed cells. Particularly, the interleukin-1 alpha (IL-1α) and IL-1 receptor antagonist (IL-1Ra) from the IL-1 family, implicated in a wide variety of inflammatory diseases, were the most induced and suppressed cytokines in KSHV-transformed KMM cells compared to the matched primary MM cells, respectively. By using reverse genetics, we showed that KSHV-encoded miRNAs mediated IL-1α induction while both miRNAs and vFLIP mediated IL-1Ra suppression. Furthermore, the GR signaling was inhibited in KSHV-transformed cells, which was mediated by vFLIP and vCyclin. Importantly, dexamethasone treatment inhibited cell proliferation, and colony formation in softagar of KMM cells but had a minimal effect on MM cells. Consequently, dexamethasone suppressed the initiation and growth of KS-like KMM tumors in mice. Mechanistically, dexamethasone suppressed IL-1α expression but induced IL-1Ra expression. Treatment with recombinant IL-1α protein was sufficient to rescue the inhibitory effect of dexamethasone while overexpression of IL-1Ra alone caused a weak growth inhibition of KMM cells. Furthermore, dexamethasone induced IκBα expression resulting in the inhibition of the classical and alternative NF-kB pathways and IL-1α expression. Taken together, these results revealed the important role of IL-1 signaling pathway in KSHV-induced inflammation and oncogenesis, which can be inhibited by dexamethasone-activated GR signaling. This study determined the mechanism of inflammation in KSHV-induced oncogenesis and identified IL-1-mediated inflammation as a potential therapeutic target for KSHV-induced malignancies.
2023-12-31 | GSE242172 | GEO
Project description:Interleukin-1, a pro-inflammatory cytokine, plays a crucial role in inflammatory disease pathogenesis. Interleukin-1 receptor antagonist knockout (IL-1Ra KO) mice spontaneously develop aortitis, arthritis, and dermatitis, and are employed as a model for human inflammatory diseases. Previous studies have shown that transferring total T cells from IL-1Ra KO mice into nude mice induces aortitis and arthritis; however, the roles of specific T cell subsets in these inflammatory responses remain unclear. In this study, we aimed to investigate the T cell subsets in IL-1Ra KO mice. We found that the proportion of PD-1+CD44+CD62L˗CD4+ T cells in the spleen and lymph nodes of IL-1Ra KO mice was significantly higher than that of wild type mice. RNA sequencing revealed elevated expression of basic helix-loop-helix family member e40 and granulocyte macrophage colony stimulating factor (GM-CSF) in splenic CD44+CD62L˗CD4+ T cells from IL-1Ra KO mice. In addition, GM-CSF production from splenic CD4+ T cells of IL-1Ra KO mice was significantly higher than that of wild type mice when stimulated with PMA and ionomycin in vitro. Notably, immunohistochemical staining showed infiltration of GM-CSF+CD4+ T cells at inflammatory sites in IL-1Ra KO mice. Our results suggest that a subset of GM-CSF+CD4+T cells emerges under IL-1 signal-enhanced inflammatory conditions.
2024-10-17 | GSE279159 | GEO
Project description:The systemic inflammatory response syndrome (SIRS) is a life-threatening medical condition characterized by a severe and generalized inflammatory state that can lead to multiple organ failure and shock. The central nervous system (CNS) regulates many features of SIRS, such as fever, cardiovascular and neuroendocrine responses. <br> <br> Central and systemic manifestations of SIRS can be induced by LPS or interleukin-1ß (IL-1ß) administration. The crucial role of IL-1ß in inflammation has been further highlighted by studies of mice lacking caspase 1 (casp1, also known as IL-1ß convertase), a protease that cleaves pro-IL-1ß into mature IL-1ß. Indeed, casp1 knockout (casp1-/-) mice survive lethal doses of LPS. The key role of IL-1ß in sickness behavior and its de-novo expression in the CNS during inflammation led us to test the hypothesis that IL-1ß plays a major role modulating the brain transcriptome during SIRS. <br> <br> We show here a genetic background environment effect caused by LPS administration in casp1-/- when compared to wild-type mice affecting the expression several genes, such as chemokines, GTPases, the metalloprotease ADAMTS1, IL-1RA, the inducible nitric oxide synthase (NOS2) and cyclooxygenase-2 (COX-2) were differentially increased by. Our findings may contribute to the understanding of the molecular changes that take place within the CNS during sepsis and SIRS and the development of new therapies for these serious conditions. Our results indicate that those genes may also play a role in several neuropsychiatric conditions in which inflammation has been implicated, and indicate that casp1 might be a potential therapeutic target for such disorders.
2008-03-02 | E-MEXP-1017 | biostudies-arrayexpress
Project description:Background: Although several studies link high levels of IL-6 and soluble IL-6 receptor (sIL-6R) with asthma severity and decreased lung function, the role of IL-6 trans-signaling (IL-6TS) in asthma is unclear. Objective: To explore the association between epithelial IL-6TS pathway activation and molecular and clinical phenotypes in asthma. Methods: Primary human bronchial epithelial cell (HBEC) air-liquid interface (ALI) cultures were stimulated with IL-6 and sIL-6R to establish an IL-6TS gene signature. Two separate RNA sequencing (RNA-seq) studies were performed: The “IL-6 vs T2 study” compared gene expression after stimulation with control medium, IL-6, IL-6/sIL-6R and IL-4/IL-13, while the “JAK1-inhibition study” addressed the effect of JAK1 inhibition on IL-6TS induced gene expression. The IL-6TS gene signature was used to stratify lung epithelial transcriptomic data obtained from asthmatics (n=103) in the U-BIOPRED cohorts by hierarchical clustering. Molecular phenotyping was based on the transcriptional profiling of epithelial brushings, pathway analysis and immunohistochemistry analysis of bronchial biopsies. Results: Activation of IL-6TS in HBEC ALI cultures reduced epithelial barrier function and induced a specific epithelial gene signature enriched in airway remodeling genes. The IL-6TS signature identified a subset (n=17) of IL-6TS High asthma patients with increased epithelial expression of IL-6TS inducible genes in absence of increased systemic levels of IL-6 and sIL-6R. The IL-6TS High subset had an increased exacerbation frequency (p=0.028), blood (>300/μl; p=0.0028) and sputum (>20%; p=0.007) eosinophilia, and submucosal infiltration of CD4 T cells, CD8 T cells (p<0.001) and macrophages (p=0.001). In bronchial brushings, TLR pathway genes were up-regulated while the expression of epithelial tight junction genes was reduced (all with q<0.05). Sputum sIL-6R levels correlated with sputum markers of remodeling and innate immune activation, in particular YKL-40, MMP3, IL-8 and IL-1β (all with q<0.001). Conclusions: Local lung epithelial IL-6TS activation in absence of type 2 airway inflammation defines a novel subset of asthmatics and may drive airway inflammation and epithelial dysfunction in these patients.
2019-01-25 | GSE113185 | GEO
Project description:Human type 1 diabetes (T1D) arises through autoimmunity towards the insulin-producing pancreatic β cells and is modeled by the BioBreeding (BB) rat. Factors associated with islet autoimmunity are dilute and difficult to directly measure in the periphery. Therefore, we previously utilized microarray-based bioassay where human T1D sera were used to induce a disease-specific gene expression signature in unrelated, healthy peripheral blood mononuclear cells (PBMC). Here we report that sera of both spontaneously diabetic BB DRlyp/lyp and diabetes inducible BB DR+/+ rats induce inflammatory signatures in healthy PBMC of non-diabetic Brown Norway (BN) rats, while allogeneic BN sera does not. Consistent with their common T1D susceptibility, transcriptional signatures of both BB sub-strains share identity, including cytokines, immune receptors and signaling molecules. However, like the human T1D signature, the DRlyp/lyp signature, which is associated with progression to diabetes, is differentiated from that of the DR+/+ by induction of many IL-1 regulated genes. Addition of IL-1RA to cultures significantly ablates the DRlyp/lyp signature. Daily treatment of DRlyp/lyp rats with human recombinant IL-1RA significantly delays onset and sera of treated animals do not induce the characteristic IL-1 signature. Consistent with the presence of immune regulation in DR+/+ rats is induction of a signature showing negative regulation of the NFκB pathway. This study supports prior human investigations of serum that reflect disease processes associated with progression to T1D and add to a growing body of evidence implicating the balance of IL-1 and IL-1RA as key factors influencing the severity and outcome of inflammatory responses. Experiment Overall Design: The induction of gene expression was accomplished by culturing the PBMCs of healthy day180 BN donor rats for 6 h at 37°C in 5% CO2 with a) 20% autologous BN plasma(10 replicates), b) allogeneic BN plasma (15 replicates), c) allogeneic DRlyp/lyp plasma (day 60, 4 replicates), or d) DR+/+ plasma (day 60, 4 replicates). Healthy BN PBMCs were also cultured with d60 DRlyp/lyp serum supplemented with IL-1RA (4 replicates) as well as autologous BN serum supplemented with IL-1B (4 replicates), to respectively block or induce IL-1 mediated gene expression. To determine if IL-1RA-treatment of DRlyp/lyp rats would result in modulation of the DRlyp/lyp signature, additional DRlyp/lyp rats were treated with hIL-1RA (n=6) or PBS (n=6). Rats were treated for 10 days, beginning at d30, then serum was collected at d40 and used to induce gene expression in PBMCs isolated from healthy d180 BN rats. Thus, there are a total of 53 chips being the addition of all the sample conditions mentioned above.
2009-12-25 | E-GEOD-19537 | biostudies-arrayexpress
Project description:Chronic prostate inflammation in patients with benign prostate hyperplasia (BPH) correlates with the severity of symptoms. How inflammation contributes to prostate enlargement and/or BPH symptoms and the underlying mechanisms remain unclear. In this study, we utilized a unique transgenic mouse model that mimics chronic non-bacterial prostatitis in men and investigated the impact of inflammation on androgen receptor (AR) in basal prostate stem cells (bPSC) and their differentiation in vivo. We found that inflammation significantly enhanced AR levels and activity in bPSC. More importantly, we identified interleukin 1 receptor antagonist (IL-1RA) as a crucial regulator of AR in bPSC during inflammation. IL-1RA was one of the top genes upregulated by inflammation, and inhibiting IL-1RA reversed the enhanced AR activity in organoids derived from inflamed bPSC. Additionally, IL-1RA appeared to activate AR by counteracting IL-1's inhibitory effect. Furthermore, using a lineage tracing model, we observed that inflammation induced bPSC proliferation and differentiation into luminal cells even under castrate conditions, indicating that AR activation driven by inflammation is sufficient to promote bPSC proliferation and differentiation. Taken together, our study uncovered novel mechanisms through which inflammation modulates AR signaling in bPSC and induces bPSC luminal differentiation that may contribute to prostate hyperplasia.
2024-10-09 | GSE271146 | GEO
Project description:Chronic prostate inflammation in patients with benign prostate hyperplasia (BPH) correlates with the severity of symptoms. How inflammation contributes to prostate enlargement and/or BPH symptoms and the underlying mechanisms remain unclear. In this study, we utilized a unique transgenic mouse model that mimics chronic non-bacterial prostatitis in men and investigated the impact of inflammation on androgen receptor (AR) in basal prostate stem cells (bPSC) and their differentiation in vivo. We found that inflammation significantly enhanced AR levels and activity in bPSC. More importantly, we identified interleukin 1 receptor antagonist (IL-1RA) as a crucial regulator of AR in bPSC during inflammation. IL-1RA was one of the top genes upregulated by inflammation, and inhibiting IL-1RA reversed the enhanced AR activity in organoids derived from inflamed bPSC. Additionally, IL-1RA appeared to activate AR by counteracting IL-1's inhibitory effect. Furthermore, using a lineage tracing model, we observed that inflammation induced bPSC proliferation and differentiation into luminal cells even under castrate conditions, indicating that AR activation driven by inflammation is sufficient to promote bPSC proliferation and differentiation. Taken together, our study uncovered novel mechanisms through which inflammation modulates AR signaling in bPSC and induces bPSC luminal differentiation that may contribute to prostate hyperplasia.
2024-06-26 | GSE269582 | GEO