scholarly journals NOTCH4 Exhibits Anti-Inflammatory Activity in Activated Macrophages by Interfering With Interferon-γ and TLR4 Signaling

2021 ◽  
Vol 12 ◽  
Author(s):  
Susana López-López ◽  
María José Romero de Ávila ◽  
Natalia Carolina Hernández de León ◽  
Francisco Ruiz-Marcos ◽  
Victoriano Baladrón ◽  
...  
Keyword(s):  
Notch Signaling ◽  
Macrophage Activation ◽  
Transcriptional Activity ◽  
Target Genes ◽  
Regulatory Element ◽  
Interferon Γ ◽  
Negative Regulator ◽  
Signal Pathways ◽  
Macrophage Response ◽  
Ifn Γ

NOTCH4 is a member of the NOTCH family of receptors whose expression is intensively induced in macrophages after their activation by Toll-like receptors (TLR) and/or interferon-γ (IFN-γ). In this work, we show that this receptor acts as a negative regulator of macrophage activation by diminishing the expression of proinflammatory cytokines, such as IL-6 and IL-12, and costimulatory proteins, such as CD80 and CD86. We have observed that NOTCH4 inhibits IFN-γ signaling by interfering with STAT1-dependent transcription. Our results show that NOTCH4 reprograms the macrophage response to IFN-γ by favoring STAT3 versus STAT1 phosphorylation without affecting their expression levels. This lower activation of STAT1 results in diminished transcriptional activity and expression of STAT1-dependent genes, including IRF1, SOCS1 and CXCL10. In macrophages, NOTCH4 inhibits the canonical NOTCH signaling pathway induced by LPS; however, it can reverse the inhibition exerted by IFN-γ on NOTCH signaling, favoring the expression of NOTCH-target genes, such as Hes1. Indeed, HES1 seems to mediate, at least in part, the enhancement of STAT3 activation by NOTCH4. NOTCH4 also affects TLR signaling by interfering with NF-κB transcriptional activity. This effect could be mediated by the diminished activation of STAT1. These results provide new insights into the mechanisms by which NOTCH, TLR and IFN-γ signal pathways are integrated to modulate macrophage-specific effector functions and reveal NOTCH4 acting as a new regulatory element in the control of macrophage activation that could be used as a target for the treatment of pathologies caused by an excess of inflammation.

scholarly journals Distinctive role of Stat3 and Erk-1/2 activation in mediating interferon-γ inhibition of TGF-β1 action

2006 ◽  
Vol 290 (5) ◽  
pp. F1234-F1240 ◽  
Author(s):  
Myrto Giannopoulou ◽  
Steven C. Iszkula ◽  
Chunsun Dai ◽  
Xiaoyue Tan ◽  
Junwei Yang ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Transforming Growth Factor ◽  
Smooth Muscle Actin ◽  
Ectopic Expression ◽  
Interferon Γ ◽  
Signal Pathways ◽  
Tubular Epithelial Cells ◽  
Plasminogen Activator Inhibitor 1 ◽  
Ifn Γ ◽  
Pai 1

Interferon-γ (IFN-γ) is a multifunctional cytokine that elicits antifibrotic activity in a variety of organs. In this study, we investigated the potential role and mechanism of IFN-γ in modulating the fibrogenic action of transforming growth factor (TGF)-β1 in tubular epithelial cells. Incubation of human proximal tubular epithelial (HKC) cells with IFN-γ inhibited TGF-β1-mediated α-smooth muscle actin (α-SMA) expression. IFN-γ also abolished TGF-β1-induced fibronectin and plasminogen activator inhibitor-1 (PAI-1) expression. To explore the mechanisms by which INF-γ inhibits TGF-β1 action, the signaling pathways that are critical for mediating the antifibrotic activity of IFN-γ were studied. Stimulation of HKC cells with IFN-γ triggered a sustained activation of Erk-1/2 and signal transducer and activator of transcription-3 (Stat3). Blockade of Erk-1/2 activation with an Mek1 inhibitor abolished the inhibitory effect of IFN-γ on α-SMA expression, whereas inhibition of Stat3 activation had no influence. Constitutive activation of Erk-1/2 by ectopic expression of activated Mek1 mimicked IFN-γ and suppressed TGF-β1-mediated α-SMA expression. Interestingly, inhibition of Stat3 activation abolished the ability of IFN-γ to attenuate TGF-β1-mediated PAI-1 and fibronectin expression in HKC cells. These findings indicate that IFN-γ is capable of antagonizing the fibrogenic actions of TGF-β1 in renal tubular epithelial cells. The antifibrotic action of IFN-γ appears to be mediated through a coordinated activation of both Erk-1/2 and Stat3 signal pathways in a mutually independent fashion.

Pre-treatment with Mycobacterium avium-derived lipids reduces the macrophage response to interferon γ in BCG-vaccinated mice

2013 ◽  
Vol 62 (7) ◽  
pp. 980-987 ◽  
Author(s):  
Daqing Yang ◽  
Beiyi Liu ◽  
Xiaoriu Hou ◽  
Delong Jiao ◽  
Xueli Li ◽  
...  
Keyword(s):  
Immune Response ◽  
Mycobacterium Avium ◽  
Inflammatory Cells ◽  
Bactericidal Effect ◽  
Interferon Γ ◽  
Macrophage Response ◽  
Murine Macrophages ◽  
Ifn Γ ◽  
Pre Treatment ◽  
Environmental Pathogens

Mycobacterium bovis Bacille Calmette–Guérin (BCG) is the current vaccine used against Mycobacterium tuberculosis (MTB) infection. However, exposure to environmental pathogens, such as Mycobacterium avium, interferes with the immune response induced by BCG vaccination. How M. avium affects the efficiency of BCG is unclear. In this study, BCG-vaccinated mice pre-treated with M. avium-derived lipids (MALs) showed a higher mycobacterial load and increased infiltration of inflammatory cells compared to control mice treated with Escherichia coli-derived lipids (ELs). Unexpectedly, there were no changes in cell proliferation or IFN-γ levels in spleen cells stimulated with protein purified derivatives (PPD) or heat-inactivated BCG in MALs-treated mice. However, pre-treatment with MALs decreased the bactericidal effect as well as the production of TNF-α and nitric oxide (NO) in murine macrophages from BCG-vaccinated mice stimulated with IFN-γ. These results suggest that MAL pre-treatment dampens the immune response against MTB and that this dampening is associated with a decreased response to IFN-γ stimulation in murine macrophages. T-lymphocyte responses, however, were unaffected.

scholarly journals Macrophage activation by lipopolysaccharide, interferon-γ and interleukin-4: effect of fatty acid metabolism

1995 ◽  
Vol 4 (1) ◽  
pp. 25-30 ◽  
Author(s):  
H. Darmani ◽  
J. L. Harwood ◽  
J. Parton ◽  
S. K. Jackson
Keyword(s):  
Nitric Oxide ◽  
Fatty Acids ◽  
Arachidonic Acid ◽  
Linoleic Acid ◽  
Macrophage Activation ◽  
Interferon Γ ◽  
Interleukin 4 ◽  
Nitric Oxide Production ◽  
Oxide Production ◽  
Ifn Γ

The aim of this study was to investigate the effects of interferon-γ and -β (IFN-γ, -β), interleukin-4 and -10 (IL-4, -10) and Hpopolysaccharide (LPS) on the metabolism and composition of phospholipid fatty acids in macrophages. Murine J774.2 macrophages were incubated with radiolabelled fatty acids and the appropriate stimulus and the incorporation and composition of the phospholipid classes was determined. IFN-γ and IL-4 specifically stimulated enhanced incorporation of [14C]-linoleic acid into the phosphatidytethanolamine fraction. IL-4 (in contrast to IFN-γ and LPS) reduced incorporation of [14C]- arachidonic acid into phosphatidylinositol. Incubation of J774.2 cells with linoleic acid significantly increased TNFα and nitric oxide production; arachidonic acid enhanced TNFα production but reduced nitric oxide production. It is concluded that IFN-γ, IL-4 and IL-10 may differentially regulate macrophage activation via effects on the metabolism of polyunsaturated fatty acids.

scholarly journals Lipidome profiling with Raman microspectroscopy identifies macrophage response to surface topographies of implant materials

2021 ◽  
Vol 118 (52) ◽  
pp. e2113694118
Author(s):  
Nora Feuerer ◽  
Julia Marzi ◽  
Eva M. Brauchle ◽  
Daniel A. Carvajal Berrio ◽  
Florian Billing ◽  
...  
Keyword(s):  
Lipid Composition ◽  
Macrophage Activation ◽  
Human Monocyte ◽  
Raman Microspectroscopy ◽  
Macrophage Response ◽  
Surface Topographies ◽  
Ifn Γ ◽  
Induced Changes ◽  
The Impact

Biomaterial characteristics such as surface topographies have been shown to modulate macrophage phenotypes. The standard methodologies to measure macrophage response to biomaterials are marker-based and invasive. Raman microspectroscopy (RM) is a marker-independent, noninvasive technology that allows the analysis of living cells without the need for staining or processing. In the present study, we analyzed human monocyte-derived macrophages (MDMs) using RM, revealing that macrophage activation by lipopolysaccharides (LPS), interferons (IFN), or cytokines can be identified by lipid composition, which significantly differs in M0 (resting), M1 (IFN-γ/LPS), M2a (IL-4/IL-13), and M2c (IL-10) MDMs. To identify the impact of a biomaterial on MDM phenotype and polarization, we cultured macrophages on titanium disks with varying surface topographies and analyzed the adherent MDMs with RM. We detected surface topography–induced changes in MDM biochemistry and lipid composition that were not shown by less sensitive standard methods such as cytokine expression or surface antigen analysis. Our data suggest that RM may enable a more precise classification of macrophage activation and biomaterial–macrophage interaction.

scholarly journals miR-449a Repression Leads to Enhanced NOTCH Signaling in TMPRSS2:ERG Fusion Positive Prostate Cancer Cells

Cancers ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 964
Author(s):  
Simone Bauer ◽  
Leonie Ratz ◽  
Doreen Heckmann-Nötzel ◽  
Adam Kaczorowski ◽  
Markus Hohenfellner ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Notch Signaling ◽  
Target Genes ◽  
Negative Regulator ◽  
Rna Seq ◽  
Hes1 Expression ◽  
Enhanced Expression ◽  
Primary Effector

About 50% of prostate cancer (PCa) tumors are TMPRSS2:ERG (T2E) fusion-positive (T2E+), but the role of T2E in PCa progression is not fully understood. We were interested in investigating epigenomic alterations associated with T2E+ PCa. Using different sequencing cohorts, we found several transcripts of the miR-449 cluster to be repressed in T2E+ PCa. This repression correlated strongly with enhanced expression of NOTCH and several of its target genes in TCGA and ICGC PCa RNA-seq data. We corroborated these findings using a cellular model with inducible T2E expression. Overexpression of miR-449a in vitro led to silencing of genes associated with NOTCH signaling (NOTCH1, HES1) and HDAC1. Interestingly, HDAC1 overexpression led to the repression of HES6, a negative regulator of the transcription factor HES1, the primary effector of NOTCH signaling, and promoted cell proliferation by repressing the cell cycle inhibitor p21. Inhibition of NOTCH as well as knockdown of HES1 reduced the oncogenic properties of PCa cell lines. Using tissue microarray analysis encompassing 533 human PCa cores, ERG-positive areas exhibited significantly increased HES1 expression. Taken together, our data suggest that an epigenomic regulatory network enhances NOTCH signaling and thereby contributes to the oncogenic properties of T2E+ PCa.

scholarly journals Influence of Interferon-γ on Salmonella Typhi Induced Macrophage Apoptosis

2020 ◽  
Vol 9 (2) ◽  
Author(s):  
Fidan I ◽  
Yesilyurt E ◽  
Kalkanci A ◽  
Erdal B ◽  
Gurelik FC ◽  
...  
Keyword(s):  
Macrophage Activation ◽  
Annexin V ◽  
Salmonella Typhi ◽  
Interferon Γ ◽  
Salmonella Infection ◽  
Rt Pcr ◽  
Caspase 1 ◽  
Macrophage Apoptosis ◽  
Ifn Γ ◽  
Induced Apoptosis

Introduction: Salmonella Typhi (S.Typhi), which causes typhoid fever, is a widespread pathogen in developing countries. Interferon-gamma (IFN-γ) is a critical cytokine in host defense against Salmonella infection. IFN-γ provides protection against Salmonella infection by inducing macrophage activation. This study was designed to determine the effect of recombinant IFN-γ (rIFN-γ) on S.Typhi induced macrophage apoptosis and to examine the effect of rIFN-g on caspase-1 expression during apoptosis. Materials and Methods: After isolation of macrophages, apoptotic cells were analyzed using both annexin V-FITC detection kit by fl ow cytometry and TUNEL technique. Caspase-1 expression was determined by RT-PCR. Results: The rIFN-γ concentrations of 100 IU/ml ve 1000 IU/ml decreased macrophage apoptosis caused by S.Typhi, 13.1 % and 6.3 % respectively. Conclusion: Consequently, we observed that rIFN-g decreased Salmonella-induced apoptosis and inhibited caspase-1 expression during apoptosis. It is considered that the modulatory effect of IFN-γ on macrophage apoptosis may impact a protective effect during Salmonella infection and this may help to abort invasive S.Typhi infections.

scholarly journals Murine Macrophages Secrete Interferon γ upon Combined Stimulation with Interleukin (IL)-12 and IL-18: A Novel Pathway of Autocrine Macrophage Activation

1998 ◽  
Vol 187 (12) ◽  
pp. 2103-2108 ◽  
Author(s):  
Markus Munder ◽  
Moisés Mallo ◽  
Klaus Eichmann ◽  
Manuel Modolell
Keyword(s):  
Macrophage Activation ◽  
Interferon Γ ◽  
Biologically Active ◽  
Efficient Production ◽  
Activated T Cells ◽  
Murine Bone Marrow ◽  
Ifn Γ ◽  
Low Levels ◽  
Oxide Synthase ◽  
Inducible Nitric Oxide

Interferon (IFN)-γ, a key immunoregulatory cytokine, has been thought to be produced solely by activated T cells and natural killer cells. In this study, we show that murine bone marrow– derived macrophages (BMMΦ) secrete large amounts of IFN-γ upon appropriate stimulation. Although interleukin (IL)-12 and IL-18 alone induce low levels of IFN-γ mRNA transcripts, the combined stimulation of BMMΦ with both cytokines leads to the efficient production of IFN-γ protein. The macrophage-derived IFN-γ is biologically active as shown by induction of inducible nitric oxide synthase as well as upregulation of CD40 in macrophages. Our findings uncover a novel pathway of autocrine macrophage activation by demonstrating that the macrophage is not only a key cell type responding to IFN-γ but also a potent IFN-γ–producing cell.

SOCS1 Cooperates with FLT3-ITD In the Development of Myeloproliferative Disease by Promoting the Escape From External Cytokine Control.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1054-1054
Author(s):  
Christian H. Brandts ◽  
Pavankumar Reddy ◽  
Bülent Sargin ◽  
Chunaram Choudhary ◽  
Carsten Muller-Tidow ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Target Genes ◽  
Conflicts Of Interest ◽  
Colony Growth ◽  
Interferon Γ ◽  
Negative Regulator ◽  
Cytokine Signaling ◽  
Myeloproliferative Disease ◽  
Clinical Prognosis ◽  
Murine Bone Marrow

Abstract Abstract 1054 Activating mutations of FLT3 such as FLT3-ITD are frequently found in AML patients and confer poor clinical prognosis. It is unclear how leukemic blasts escape cytokine control, which regulates normal hematopoiesis. We have recently demonstrated that FLT3-ITD, when localized to the endoplasmic reticulum, aberrantly activates STAT5. Here we show that one of the target genes induced by STAT5 is SOCS1, a potent negative regulator of cytokine signaling and known tumor suppressor gene. Importantly, a significantly increased SOCS1 expression was found in FLT3-ITD+ AML. While SOCS1 expression in murine bone marrow severely impaired cytokineinduced colony growth, it failed to inhibit FLT3-ITD supported colony growth, indicating resistance of FLT3-ITD to SOCS1. Furthermore, SOCS1 co-expression inhibited interferon-γ signaling and protected FLT3-ITD hematopoietic cells from interferon-γ mediated growth inhibitory effects. In a murine bone marrow transplantation model, the co-expression of SOCS1 and FLT3-ITD significantly shortened the latency of a myeloproliferative disease compared to FLT3-ITD alone (p<0.01). Mechanistically, SOCS proteins shield FLT3-ITD from external cytokine control, thereby promoting malignant transformation. The data demonstrate that SOCS1 acts as a conditional oncogene, providing novel molecular insights into cytokine resistance in oncogenic transformation. Restoring cytokine control may provide a new way of therapeutic intervention. Disclosures: No relevant conflicts of interest to declare.

Macrophage activation syndrome: characteristic findings on liver biopsy illustrating the key role of activated, IFN-γ-producing lymphocytes and IL-6- and TNF-α-producing macrophages

Blood ◽  
2005 ◽  
Vol 105 (4) ◽  
pp. 1648-1651 ◽  
Author(s):  
An D. Billiau ◽  
Tania Roskams ◽  
Rita Van Damme-Lombaerts ◽  
Patrick Matthys ◽  
Carine Wouters
Keyword(s):  
Macrophage Activation Syndrome ◽  
Macrophage Activation ◽  
Interferon Γ ◽  
Effector Pathway ◽  
Tnf Α ◽  
Ifn Γ ◽  
Factor Α ◽  
Necrosis Factor ◽  
Activation Syndrome

Abstract Macrophage activation syndrome (MAS) is a rare and potentially fatal disorder, thought to result from uncontrolled activation and proliferation of T cells and excessive activation of macrophages. The term MAS designates a clinicopathologic entity that occurs in different hemophagocytic syndromes (HSs). Primary hemophagocytic lymphohistiocytosis (HLH) is recognized to have an immunogenetic basis, but in the secondary HS (also referred to as secondary HLH), the cause is unknown. The pathogenesis of the accelerated disease phase typical of MAS remains incompletely understood. This report describes the immunohistochemical findings on liver tissues from 5 children, each of whom presented with MAS in the context of a different type of HS. The data provide direct evidence for the involvement of activated CD8+ lymphocytes through the production of interferon-γ and of macrophages through hemophagocytosis and production of interleukin 6 and tumor necrosis factor-α, and underscore the view that MAS in different HSs share a common effector pathway. (Blood. 2005;105:1648-1651)

scholarly journals Engrailed-1 Negatively Regulates β-Catenin Transcriptional Activity by Destabilizing β-Catenin via a Glycogen Synthase Kinase-3β–independent Pathway

2006 ◽  
Vol 17 (6) ◽  
pp. 2572-2580 ◽  
Author(s):  
Liora Bachar-Dahan ◽  
Janna Goltzmann ◽  
Abraham Yaniv ◽  
Arnona Gazit
Keyword(s):  
Transcription Factors ◽  
Transcriptional Activity ◽  
Target Genes ◽  
Glycogen Synthase ◽  
Proteasomal Degradation ◽  
Negative Regulator ◽  
Glycogen Synthase Kinase ◽  
Repressive Effect ◽  
Gsk 3Β ◽  
Wnt Signal

The Wnt signaling pathway plays a major role in development, and upon deregulation it is implicated in neoplasia. The hallmark of the canonical Wnt signal is the protection of β-catenin from ubiquitination and proteasomal degradation induced by glycogen synthase kinase (GSK)-3β inhibition. The stabilized β-catenin translocates to the nucleus where it binds to T-cell factor/lymphoid enhancer factor (TCF/LEF) transcription factors, activating the expression of Wnt target genes. In the absence of Wnt signal, TCF/LEF bind to Groucho (Gro)/TLE corepressors and repress Wnt target genes. Gro/TLE bind also to Engrailed (En) transcription factors mediating En-repressive activity on En target genes. Here, we present data suggesting that En-1 serves also as a negative regulator of β-catenin transcriptional activity; however, its repressive effect is independent of Gro/TLE. Our data suggest that En-1 acts by destabilizing β-catenin via a proteasomal degradation pathway that is GSK-3β–independent. Moreover, because En-1-mediated β-catenin degradation is also Siah independent, our data imply that En-1 exerts its repressive effect by a novel mechanism negatively controlling the level of β-catenin.

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