Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Pro- and anti-tumorigenic capacity of immunoproteasomes in shaping the tumor microenvironment

ABSTRACT: Apart from the constitutive proteasome, the immunoproteasome that comprises the three proteolytic subunits LMP2, MECL-1 and LMP7 is expressed in most immune cells. In this study we describe two opposing roles for immunoproteasomes in regulating the tumor microenvironment. During chronic inflammation, immunoproteasomes modulated the expression of pro-tumorigenic cytokines and chemokines and enhanced infiltration of innate immune cells that led to the onset of colitis-associated carcinogenesies (CAC). In ulcerative colitis (UC) patients with high risk for CAC, immunoproteasome-induced pro-tumorigenic mediators were highly upregulated. Interestingly, the role for the same enzymatic complex in melanoma tumors is relatively unknown. We found that the high expression of immunoproteasomes in human melanoma was associated with better prognosis. Our data revealed that the immunoproteasome has a strong anti-tumorigenic function in cancer types with non-inflammatory microenvironment such as melanoma. CD8+ cytotoxic T lymphocytes (CTLs) from immunoproteasome-deficient mice were reduced during T cell homeostasis and were not able to combat melanoma efficiently. Our results indicate that the immunoproteasome exhibits either pro- or anti-tumoral properties in a context-dependent manner.

ORGANISM(S): Homo sapiens

PROVIDER: GSE150979 | GEO | 2021/08/18

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Immunoproteasome dysfunction augments alternative polarization of alveolar macrophages

Project description:The proteasome is a central regulatory hub for intracellular signaling by degrading numerous signaling mediators. Immunoproteasomes are specialized types of proteasomes known to be involved in shaping adaptive immune responses, but their role for innate immune signaling is elusive. Here, we analyzed immunoproteasome function for polarization of alveolar macrophages which are highly specialized tissue macrophages of the alveolar surface of the lung. Classical activation (M1 polarization) of primary alveolar macrophages by LPS/IFNÎ³ transcriptionally induced all three immunoproteasome subunits LMP2, LMP7, and MECL-1. In contrast, IL-4 triggered alternative (M2) activation was accompanied by posttranscriptional upregulation of LMP2 and LMP7. Accordingly, immunoproteasome activity increased in M1 cells, and to some extent under M2 conditions. Analyzing the polarization capability from LMP7 deficient mice revealed no effect on the LPS/IFNÎ³ triggered M1 profile, but uncovered a distorted M2 profile for IL-4 stimulated LMP7-/- alveolar macrophages as characterized by increased M2 marker gene expression and CCL17 cytokine release. This shift in immunoproteasome-dependent M2 polarization was accompanied by amplified AKT/STAT6 activation and IRF4 expression in LMP7-/- alveolar macrophages. IL-13 stimulation of LMP7 deficient cells induced a similar M2 skewed profile and IL4RÎ± protein expression was generally elevated in LMP7-/- alveolar macrophages, indicating that amplified IL4R signaling in immunoproteasome defective cells may contribute to augmented M2 polarization. Importantly, treatment with an LMP7-specific proteasome inhibitor recapitulated the findings of genetic LMP7 inactivation. Our results thus suggest a novel role of immunoproteasome function for regulating innate immune function of macrophages by limiting IL4R expression and signaling. Expression data of M0 and M2 macrophages derived from Lmp7 k.o. and control animals

2016-06-29 | E-GEOD-72000 | biostudies-arrayexpress

Immunoproteasome dysfunction augments alternative polarization of alveolar macrophages

Project description:The proteasome is a central regulatory hub for intracellular signaling by degrading numerous signaling mediators. Immunoproteasomes are specialized types of proteasomes known to be involved in shaping adaptive immune responses, but their role for innate immune signaling is elusive. Here, we analyzed immunoproteasome function for polarization of alveolar macrophages which are highly specialized tissue macrophages of the alveolar surface of the lung. Classical activation (M1 polarization) of primary alveolar macrophages by LPS/IFNγ transcriptionally induced all three immunoproteasome subunits LMP2, LMP7, and MECL-1. In contrast, IL-4 triggered alternative (M2) activation was accompanied by posttranscriptional upregulation of LMP2 and LMP7. Accordingly, immunoproteasome activity increased in M1 cells, and to some extent under M2 conditions. Analyzing the polarization capability from LMP7 deficient mice revealed no effect on the LPS/IFNγ triggered M1 profile, but uncovered a distorted M2 profile for IL-4 stimulated LMP7-/- alveolar macrophages as characterized by increased M2 marker gene expression and CCL17 cytokine release. This shift in immunoproteasome-dependent M2 polarization was accompanied by amplified AKT/STAT6 activation and IRF4 expression in LMP7-/- alveolar macrophages. IL-13 stimulation of LMP7 deficient cells induced a similar M2 skewed profile and IL4Rα protein expression was generally elevated in LMP7-/- alveolar macrophages, indicating that amplified IL4R signaling in immunoproteasome defective cells may contribute to augmented M2 polarization. Importantly, treatment with an LMP7-specific proteasome inhibitor recapitulated the findings of genetic LMP7 inactivation. Our results thus suggest a novel role of immunoproteasome function for regulating innate immune function of macrophages by limiting IL4R expression and signaling.

2016-06-29 | GSE72000 | GEO

Subunit-specific vs. non-selective proteasome modulation in limiting inflammation in experimental colitis

Project description:Inflammatory bowel disease (IBD), comprising Crohn´s disease and Ulcerative colitis, is characterized by chronic relapsing inflammation of the gut. It has been shown that increased proteasomal activity is associated with the expression of immunoproteasomes, which enhances NF-kB activation and thus promotes inflammation in IBD-patients. Here, we investigate whether modulation of the proteasomal activity is a suitable therapeutic approach to limit inflammation in colitis. This concept was tested in two different experimental setups. First, development of dextran sulfate sodium (DSS)-induced colitis was tested in lmp7-/--mice, which lack the essential immunoproteasome-subunit LMP7 or in wildtype-mice treated with the proteasome inhibitor bortezomib. Compared to WT mice, lmp7-/- mice revealed significantly attenuated colitis resulting from reduced NF-kB activation in the absence of LMP7. Further, treatment with bortezomib revealed dose-dependent amelioration of DSS-induced inflammation. In both approaches proteasome modulation limited the infiltration of neutrophils, consequently reducing tissue damage. In summary our experiments demonstrate that modulation of the proteasomal activity is effective in attenuating experimental colitis. In particular, our data suggest that the immunoproteasome-subunit LMP7 is a suitable target for the therapy of IBD.

2010-07-07 | GSE18163 | GEO

Subunit-specific vs. non-selective proteasome modulation in limiting inflammation in experimental colitis

Project description:Inflammatory bowel disease (IBD), comprising CrohnM-BM-4s disease and Ulcerative colitis, is characterized by chronic relapsing inflammation of the gut. It has been shown that increased proteasomal activity is associated with the expression of immunoproteasomes, which enhances NF-kB activation and thus promotes inflammation in IBD-patients. Here, we investigate whether modulation of the proteasomal activity is a suitable therapeutic approach to limit inflammation in colitis. This concept was tested in two different experimental setups. First, development of dextran sulfate sodium (DSS)-induced colitis was tested in lmp7-/--mice, which lack the essential immunoproteasome-subunit LMP7 or in wildtype-mice treated with the proteasome inhibitor bortezomib. Compared to WT mice, lmp7-/- mice revealed significantly attenuated colitis resulting from reduced NF-kB activation in the absence of LMP7. Further, treatment with bortezomib revealed dose-dependent amelioration of DSS-induced inflammation. In both approaches proteasome modulation limited the infiltration of neutrophils, consequently reducing tissue damage. In summary our experiments demonstrate that modulation of the proteasomal activity is effective in attenuating experimental colitis. In particular, our data suggest that the immunoproteasome-subunit LMP7 is a suitable target for the therapy of IBD. Microarray experiments were performed as dual-color hybridizations. To compensate for dye-specific effects, a dye-reversal color-swap was applied. Samples of proximal colon were cut longitudinally, washed in PBS, shortly incubated in 4M Guanidinium-isothiocyanat and transferred to TRIzol (Invitrogen).

2010-07-06 | E-GEOD-18163 | biostudies-arrayexpress

Pro- and anti-tumorigenic capacity of immunoproteasomes in shaping the tumor microenvironment

Project description:Pro- and anti-tumorigenic capacity of immunoproteasomes in shaping the tumor microenvironment

| PRJNA634311 | ENA

Reduced transformation of intestinal smooth muscle cells into fibroblasts inhibit intestinal wound healing and colitis-associated cancer in ageing mice

Project description:Although ageing is usually regarded as a high risk of cancer, the relationship between ageing stromal microenvironment and spontaneous cancer initiation is poorly understood. In murine models of DSS-induced colitis and AOM/DSS-induced colitis-associated cancer (CAC), we found ageing significantly inhibit both intestinal wound healing and simultaneous CAC initiation. In young mice, through conditional lineage tracing, a novel and important source of fibroblasts transformed from intestinal smooth muscle cells (ISMCs) was identified during intestinal wound healing, which existed persistently in CAC. We further found that activation of YAP/TAZ in ISMCs is required for their transformation into fibroblasts. However, in ageing intestinal microenvironment, the failure of YAP/TAZ activation in ISMCs led to reduced fibroblast numbers, orchestrating the inhibition of wound healing and simultaneous inhibition of CAC initiation. Collectively, our work revealed an important role of ageing stromal microenvironment in intestinal wound healing and CAC development. Meanwhile, our work also discovered an important source of fibroblasts involved in colitis and CAC.

2023-08-21 | GSE143693 | GEO

Caffeine modulates immunoproteasome activity and content in colorectal adenocarcinoma cells

Project description:Proteasomes hydrolyze most intracellular proteins. Immunoproteasome is a specific form of proteasome implicated in inflammation, cancer and autoimmune diseases. Modulation of immunoproteasome activity and content is a promising direction for the management of socially important pathologies. Using previously obtained reporter colorectal cancer cell lines, we tested how various commonly used compounds including ibuprofen, acetylsalicylic acid, vitamin C, caffeine and others, affect immunoproteasome expression. Methods: Immunoproteasome subunit expression was assessed by flow cytometry, qPCR and Western blot. Proteasome activity was tested using fluorogenic substrates and the activity probe. Transcriptome analysis was performed to identify patterns of gene expression changes. Results: Among the tested compounds caffeine was the only drug that revealed modest reduction in quantity of immunoproteasomes. The effect of caffeine on immunoproteasomes varied between cell lines and was stronger as a result of prolonged treatment. The reduction of immunoproteasome content in cells treated with caffeine coincided with decreased expression of immunoproteasome subunits and downregulation of Nrf3 transcription factor and a PAC4 proteasome assembly chaperone. Moreover, decreased expression of immunoproteasome subunits in cells treated with caffeine coincided with the reduction of oxidative stress levels. Caffeine did not affect the degradation of immunoproteasomes by autophagy. Conclusions: Modulation of immunoproteasome expression by caffeine might help to optimize existing and develop novel strategies for the treatment of colorectal cancer and several autoimmune diseases.

2024-10-22 | GSE279800 | GEO

Targeting Immunoproteasome in Macrophages Suppresses M1 Polarization and Ameliorates Experimental Emphysema via Activating NRF1 and NRF2-P62 Axis

Project description:Chronic obstructive pulmonary disease (COPD) stands as the prevailing chronic airway ailment, characterized by chronic bronchitis and emphysema. Current medications fall short in treatment of these diseases, underscoring the urgent need for effective therapy. Prior research indicated immunoproteasome inhibition can alleviate various inflammatory diseases by modulating immune cell functions. However, its therapeutic potential in COPD remains largely unexplored. Here, we observed elevated expression of immunoproteasome subunits LMP2 and LMP7 in bronchoalveolar lavage (BAL) macrophages collected from mouse with LPS/elastase-induced emphysema and M1 polarized macrophages in vitro. Subsequently, intranasal administration of the immunoproteasome-specific inhibitor ONX-0914 significantly mitigated emphysema-associated airway inflammation and improved lung function in mice, by suppressing M1 macrophage polarization. Mechanistically, ONX-0914 activated autophagy, and endoplasmic reticulum (ER) stress was not necessary for ONX- 0914-induced M1 suppression. Intriguingly, ONX-0914 upregulated the autophagy receptor p62/SQSTM1, which proved vital for the inhibitory effect of ONX-0914 on M1 polarization. Additionally, our research identified that the nuclear factor erythroid 2-related factor-2 (NRF2), but not NRF1, was responsible for the induction of p62. Finally, silencing both NRF1 and NRF2 partially counteracted ONX-0914-mediated M1 polarization inhibition. In summary, our findings suggest that targeting the immunoproteasome in macrophages holds promise as a therapeutic strategy for emphysema.

2024-05-31 | GSE266962 | GEO