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.

Fas/APO-1 (CD95)–Mediated Apoptosis Is Activated by Interferon-γ and Interferon- in Interleukin-6 (IL-6)–Dependent and IL-6–Independent Multiple Myeloma Cell Lines

Blood ◽  
1998 ◽  
Vol 92 (8) ◽  
pp. 2914-2923 ◽  
Author(s):  
Helena Spets ◽  
Patrik Georgii-Hemming ◽  
Jan Siljason ◽  
Kenneth Nilsson ◽  
Helena Jernberg-Wiklund
Keyword(s):  
Multiple Myeloma ◽  
Cell Lines ◽  
Poor Response ◽  
Antigen Expression ◽  
Myeloma Cell ◽  
Interferon Γ ◽  
Dependent Manner ◽  
Multiple Myeloma Cell ◽  
Ifn Γ ◽  
Induced Apoptosis

Abstract A poor response to Fas-induced apoptosis is evident in some multiple myeloma (MM) cell lines and primary cells. In this study, we have examined the possibility to increase the sensitivity to Fas-induced apoptosis by pretreatment of MM cells with interferon-γ (IFN-γ) or interferon- (IFN-). Both IFN-γ and IFN- markedly increased the Fas-induced apoptosis in all cell lines tested (U-266-1970, U-266-1984, and U-1958). In the U-266-1970 and U-1958 cell lines, pretreatment with either IFN-γ or IFN- also inhibited proliferation in a dose-dependent manner. In contrast, IFN-γ activation of the Fas death pathway in the U-266-1984 cells was not accompanied by growth inhibition. Incubation with the IFNs increased the Fas antigen expression in one of three cell lines but did not alter the expression of Bcl-2 or Bax. The IFNs are important regulators of growth and survival in MM cells. Our results suggest that activation of Fas-mediated apoptosis is a novel mechanism by which the IFNs exert inhibitory effects on MM cells. © 1998 by The American Society of Hematology.

scholarly journals Inactivation of the Fanconi Anemia Group C Gene Augments Interferon-γ–Induced Apoptotic Responses in Hematopoietic Cells

Blood ◽  
1997 ◽  
Vol 90 (3) ◽  
pp. 974-985 ◽  
Author(s):  
R. Keaney Rathbun ◽  
Gregory R. Faulkner ◽  
Marika H. Ostroski ◽  
Tracy A. Christianson ◽  
Grant Hughes ◽  
...  
Keyword(s):  
Fanconi Anemia ◽  
Inhibitory Effect ◽  
Interferon Γ ◽  
Interferon Response ◽  
Low Doses ◽  
Order Of Magnitude ◽  
Ifn Γ ◽  
Fas Pathway ◽  
Anemia Group ◽  
Induced Apoptosis

Abstract Hematopoietic progenitor cells (HPC) from mice nullizygous at the Fanconi anemia (FA) group C locus (FAC −/−) are hypersensitive to the mitotic inhibitory effects of interferon (IFN-γ). We tested the hypothesis that HPC from the bone marrow of Fanconi group C children are similarly hypersensitive and that the fas pathway is involved in affecting programmed cell death in response to low doses of IFN-γ. In normal human and murine HPC, IFN-γ primed the fas pathway and induced both fas and interferon response factor-1 (IRF-1) gene expression. These IFN-γ-induced apoptotic responses in HPC from the marrow of a child with FA of the C group (FA-C) and in FAC −/− mice occurred at significantly lower IFN doses (by an order of magnitude) than did the apoptotic responses of normal HPC. Treatment of FA-C CD34+ cells with low doses of recombinant IFN-γ, inhibited growth of colony forming unit granulocyte-macrophage and burst-forming unit erythroid, while treatment with blocking antibodies to fas augmented clonal growth and abrogated the clonal inhibitory effect of IFN-γ. Transfer of the normal FAC gene into FA-C B-cell lines prevented mitomycin C–induced apoptosis, but did not suppress fas expression or inhibit the primed fas pathway. However, the kinetics of Stat1-phosphate decay in IFN-γ–treated cells was prolonged in mutant cells and was normalized by transduction of the normal FAC gene. Therefore, the normal FAC protein serves, in part, to modulate IFN-γ signals. HPC bearing inactivating mutations of FAC fail to normally modulate IFN-γ signals and, as a result, undergo apoptosis executed through the fas pathway.

Role of NF-κB in β-cell death

2008 ◽  
Vol 36 (3) ◽  
pp. 334-339 ◽  
Author(s):  
Danielle Melloul
Keyword(s):  
Cell Death ◽  
Lymphocytic Infiltration ◽  
Nuclear Factor Κb ◽  
Interferon Γ ◽  
Cell Protection ◽  
Β Cells ◽  
Β Cell ◽  
Ifn Γ ◽  
Induced Apoptosis

Apoptotic β-cell death appears to be central to the pathogenesis of Type 1 diabetes mellitus and in islet graft rejection. The β-cell destruction is partially mediated by cytokines, such as IL-1β (interleukin 1β), TNFα (tumour necrosis factor α) and IFN-γ (interferon γ). IL-1β and TNFα mediate activation of the transcription factor NF-κB (nuclear factor κB) pathway. Use of a degradation-resistant NF-κB protein inhibitor (ΔNIκBα), specifically expressed in β-cells, significantly reduced IL-1β+IFN-γ-induced apoptosis. Moreover, in vivo, it protected against multiple low-dose streptozocin-induced diabetes, with reduced intra-islet lymphocytic infiltration. Thus β-cell-specific activation of NF-κB is a key event in the progressive loss of β-cells in diabetes. Inhibition of this process could be a potential effective strategy for β-cell protection.

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.

Bystander destruction of hematopoietic progenitor and stem cells in a mouse model of infusion-induced bone marrow failure

Blood ◽  
2004 ◽  
Vol 104 (6) ◽  
pp. 1671-1678 ◽  
Author(s):  
Jichun Chen ◽  
Karen Lipovsky ◽  
Felicia M. Ellison ◽  
Rodrigo T. Calado ◽  
Neal S. Young
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Bone Marrow Failure ◽  
Marrow Cell ◽  
Annexin V ◽  
Interferon Γ ◽  
Hematopoietic Progenitor ◽  
Ifn Γ

Abstract Infusion of parental lymph node (LN) cells into sublethally irradiated hybrid F1 recipients created a murine model for bone marrow (BM) failure. Affected animals developed fatal pancytopenia within 2 to 3 weeks, accompanied by BM oligoclonal T-cell infiltration and severe marrow hypoplasia indicated by approximately 10-fold declines in total BM cellularity, 15-fold declines in BM Lin-Sca1+c-Kit+ cells, 100-fold declines in spleen colony-forming units, and 100-fold declines in hematopoietic progenitor and stem cells as estimated by irradiation protection in vivo. LN cells of both H2b/b and H2d/d haplotypes were effectors. Serum interferon-γ (IFN-γ) concentration increased 2- to 3-fold. Marrow cells were severely apoptotic, with high proportions of Fas+ and annexin V+ cells. Cotransplantation of 5 × 105 BM cells from clinically affected donors and 106 BM cells from H2 identical healthy mice could not rescue lethally irradiated recipients. Recipients had significantly lower cellularity in peripheral blood and BM, and cell mixtures failed to produce a stromal feeder layer to support marrow cell growth in vitro. Pathogenic T cells from donors after BM failure appeared capable of destroying hematopoietic progenitor, stem, and stromal cells from fully compatible healthy donors as “innocent bystanders.” This effect can be partially abrogated by anti-IFN-γ antibody. (Blood. 2004;104:1671-1678)

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 Inactivation of the Fanconi Anemia Group C Gene Augments Interferon-γ–Induced Apoptotic Responses in Hematopoietic Cells

Blood ◽  
1997 ◽  
Vol 90 (3) ◽  
pp. 974-985 ◽  
Author(s):  
R. Keaney Rathbun ◽  
Gregory R. Faulkner ◽  
Marika H. Ostroski ◽  
Tracy A. Christianson ◽  
Grant Hughes ◽  
...  
Keyword(s):  
Fanconi Anemia ◽  
Inhibitory Effect ◽  
Interferon Γ ◽  
Interferon Response ◽  
Low Doses ◽  
Order Of Magnitude ◽  
Ifn Γ ◽  
Fas Pathway ◽  
Anemia Group ◽  
Induced Apoptosis

Hematopoietic progenitor cells (HPC) from mice nullizygous at the Fanconi anemia (FA) group C locus (FAC −/−) are hypersensitive to the mitotic inhibitory effects of interferon (IFN-γ). We tested the hypothesis that HPC from the bone marrow of Fanconi group C children are similarly hypersensitive and that the fas pathway is involved in affecting programmed cell death in response to low doses of IFN-γ. In normal human and murine HPC, IFN-γ primed the fas pathway and induced both fas and interferon response factor-1 (IRF-1) gene expression. These IFN-γ-induced apoptotic responses in HPC from the marrow of a child with FA of the C group (FA-C) and in FAC −/− mice occurred at significantly lower IFN doses (by an order of magnitude) than did the apoptotic responses of normal HPC. Treatment of FA-C CD34+ cells with low doses of recombinant IFN-γ, inhibited growth of colony forming unit granulocyte-macrophage and burst-forming unit erythroid, while treatment with blocking antibodies to fas augmented clonal growth and abrogated the clonal inhibitory effect of IFN-γ. Transfer of the normal FAC gene into FA-C B-cell lines prevented mitomycin C–induced apoptosis, but did not suppress fas expression or inhibit the primed fas pathway. However, the kinetics of Stat1-phosphate decay in IFN-γ–treated cells was prolonged in mutant cells and was normalized by transduction of the normal FAC gene. Therefore, the normal FAC protein serves, in part, to modulate IFN-γ signals. HPC bearing inactivating mutations of FAC fail to normally modulate IFN-γ signals and, as a result, undergo apoptosis executed through the fas pathway.

scholarly journals Role of Na+/Ca2+ Exchangers in Therapy Resistance of Medulloblastoma Cells

2017 ◽  
Vol 42 (3) ◽  
pp. 1240-1251 ◽  
Author(s):  
Lisann Pelzl ◽  
Zohreh Hosseinzadeh ◽  
Tamer al-Maghout ◽  
Yogesh Singh ◽  
Itishri Sahu ◽  
...  
Keyword(s):  
Annexin V ◽  
Therapy Resistance ◽  
Transport Processes ◽  
Protein Abundance ◽  
Rt Pcr ◽  
Transcript Levels ◽  
Cell Current ◽  
Radiation Induced ◽  
Induced Apoptosis

Background/Aims: Alterations of cytosolic Ca2+-activity ([Ca2+]i) are decisive in the regulation of tumor cell proliferation, migration and survival. Transport processes participating in the regulation of [Ca2+]i include Ca2+ extrusion through K+-independent (NCX) and/or K+-dependent (NCKX) Na+/Ca2+-exchangers. The present study thus explored whether medulloblastoma cells express Na+/Ca2+-exchangers, whether expression differs between therapy sensitive D283 and therapy resistant UW228-3 medulloblastoma cells, and whether Na+/Ca2+-exchangers participate in the regulation of cell survival. Methods: In therapy sensitive D283 and therapy resistant UW228-3 medulloblastoma cells transcript levels were estimated by RT-PCR, protein abundance by Western blotting, cytosolic Ca2+-activity ([Ca2+]i) from Fura-2-fluorescence, Na+/ Ca2+-exchanger activity from the increase of [Ca2+]i (Δ[Ca2+]i) and from whole cell current (Ica) following abrupt replacement of Na+ containing (130 mM) and Ca2+ free by Na+ free and Ca2+ containing (2 mM) extracellular perfusate as well as cell death from PI -staining and annexin-V binding in flow cytometry. Results: The transcript levels of NCX3, NCKX2, and NCKX5, protein abundance of NCX3, slope and peak of Δ[Ca2+]i as well as Ica were significantly lower in therapy sensitive D283 than in therapy resistant UW228-3 medulloblastoma cells. The Na+/Ca2+-exchanger inhibitor KB-R7943 (10 µM) significantly blunted Δ[Ca2+]i, and augmented the ionizing radiation-induced apoptosis but did not significantly modify clonogenicity of medulloblastoma cells. Apoptosis was further enhanced by NCX3 silencing. Conclusions: Na+/Ca2+-exchanger activity significantly counteracts apoptosis but does not significantly affect clonogenicity after radiation of medulloblastoma cells.

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.

Fas/APO-1 (CD95)–Mediated Apoptosis Is Activated by Interferon-γ and Interferon- in Interleukin-6 (IL-6)–Dependent and IL-6–Independent Multiple Myeloma Cell Lines

Blood ◽  
1998 ◽  
Vol 92 (8) ◽  
pp. 2914-2923 ◽  
Author(s):  
Helena Spets ◽  
Patrik Georgii-Hemming ◽  
Jan Siljason ◽  
Kenneth Nilsson ◽  
Helena Jernberg-Wiklund
Keyword(s):  
Multiple Myeloma ◽  
Cell Lines ◽  
Poor Response ◽  
Antigen Expression ◽  
Myeloma Cell ◽  
Interferon Γ ◽  
Dependent Manner ◽  
Multiple Myeloma Cell ◽  
Ifn Γ ◽  
Induced Apoptosis

A poor response to Fas-induced apoptosis is evident in some multiple myeloma (MM) cell lines and primary cells. In this study, we have examined the possibility to increase the sensitivity to Fas-induced apoptosis by pretreatment of MM cells with interferon-γ (IFN-γ) or interferon- (IFN-). Both IFN-γ and IFN- markedly increased the Fas-induced apoptosis in all cell lines tested (U-266-1970, U-266-1984, and U-1958). In the U-266-1970 and U-1958 cell lines, pretreatment with either IFN-γ or IFN- also inhibited proliferation in a dose-dependent manner. In contrast, IFN-γ activation of the Fas death pathway in the U-266-1984 cells was not accompanied by growth inhibition. Incubation with the IFNs increased the Fas antigen expression in one of three cell lines but did not alter the expression of Bcl-2 or Bax. The IFNs are important regulators of growth and survival in MM cells. Our results suggest that activation of Fas-mediated apoptosis is a novel mechanism by which the IFNs exert inhibitory effects on MM cells. © 1998 by The American Society of Hematology.

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