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.

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.

Continuous in vivo infusion of interferon-gamma (IFN-γ) preferentially reduces myeloid progenitor numbers and enhances engraftment of syngeneic wild-type cells in Fancc-/- mice

Blood ◽  
2004 ◽  
Vol 104 (4) ◽  
pp. 1204-1209 ◽  
Author(s):  
Xiaxin Li ◽  
Yanzhu Yang ◽  
Jin Yuan ◽  
Ping Hong ◽  
Brian Freie ◽  
...  
Keyword(s):  
Stem Cells ◽  
Fanconi Anemia ◽  
Cancer Susceptibility ◽  
Phase 1 ◽  
Interferon Γ ◽  
Wild Type ◽  
Ifn Γ ◽  
Anemia Group

AbstractFanconi anemia (FA) is characterized by bone marrow (BM) failure and cancer susceptibility. Identification of the cDNAs of many FA complementation types allows the potential of using gene transfer technology to introduce functional cDNAs as transgenes into autologous stem cells and provide a cure for the BM failure in FA patients. Previous studies in FA murine models and in a phase 1 clinical trial suggest that myelopreparation is required for significant engraftment of exogenous, genetically corrected stem cells. Since myeloid progenitors from Fancc-/- mice and human Fanconi anemia group C protein (FANCC) patients have increased apoptosis in response to interferon γ (IFN-γ) in vitro, we hypothesized that IFN-γ may be useful as a nongenotoxic, myelopreparative conditioning agent. To test this hypothesis, IFN-γ was administered as a continuous infusion to Fancc-/- and wild-type (WT) mice for 1 week. Primitive and mature myeloid lineages were preferentially reduced in IFN-γ-treated Fancc-/- mice. Further, IFN-γ conditioning of Fancc-/- recipients was sufficient as a myelopreparative regimen to allow consistent engraftment of isogenic WT repopulating stem cells. Collectively, these data demonstrate that Fancc-/- hematopoietic cell populations have increased hypersensitivity to IFN-γ in vivo and that IFN-γ conditioning may be useful as a nongenotoxic strategy for myelopreparation in this disorder. (Blood. 2004;104:1204-1209)

IFN-γ + LPS induction of iNOS is modulated by ERK, JNK/SAPK, and p38 mapk in a mouse macrophage cell line

2001 ◽  
Vol 280 (3) ◽  
pp. C441-C450 ◽  
Author(s):  
Edward D. Chan ◽  
David W. H. Riches
Keyword(s):  
Nitric Oxide ◽  
Cell Line ◽  
Inhibitory Effect ◽  
Interferon Γ ◽  
Dominant Negative ◽  
Jnk Pathway ◽  
Mutant Proteins ◽  
Inos Promoter ◽  
Ifn Γ ◽  
Inos Induction

Nitric oxide (NO·) produced by inducible nitric oxide synthase (iNOS) mediates a number of important physiological and pathophysiological processes. The objective of this investigation was to examine the role of mitogen-activated protein kinases (MAPKs) in the regulation of iNOS and NO· by interferon-γ (IFN-γ) + lipopolysaccharide (LPS) in macrophages using specific inhibitors and dominant inhibitory mutant proteins of the MAPK pathways. The signaling pathway utilized by IFN-γ in iNOS induction is well elucidated. To study signaling pathways that are restricted to the LPS-signaling arm, we used a subclone of the parental RAW 264.7 cell line that is unresponsive to IFN-γ alone with respect to iNOS induction. In this RAW 264.7γNO(−) subclone, IFN-γ and LPS are nevertheless required for synergistic activation of the iNOS promoter. We found that extracellular signal-regulated kinase (ERK) augmented and p38 mapk inhibited IFN-γ + LPS induction of iNOS. Dominant-negative MAPK kinase-4 inhibited iNOS promoter activation by IFN-γ + LPS, also implicating the c-Jun NH2-terminal kinase (JNK) pathway in mediating iNOS induction. Inhibition of the ERK pathway markedly reduced IFN-γ + LPS-induced tumor necrosis factor-α protein expression, providing a possible mechanism by which ERK augments iNOS expression. The inhibitory effect of p38 mapk appears more complex and may be due to the ability of p38 mapk to inhibit LPS-induced JNK activation. These results indicate that the MAPKs are important regulators of iNOS-NO· expression by IFN-γ + LPS.

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.

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.

The Radioprotective Effects of Bu-Zhong-Yi-Qi-Tang: A Prescription of Traditional Chinese Medicine

2002 ◽  
Vol 30 (01) ◽  
pp. 127-137 ◽  
Author(s):  
Sung-Ho Kim ◽  
Song-Eun Lee ◽  
Heon Oh ◽  
Se-Ra Kim ◽  
Sung-Tae Yee ◽  
...  
Keyword(s):  
Inhibitory Effect ◽  
Oriental Medicine ◽  
Low Doses ◽  
Radix Ginseng ◽  
Hematopoietic Organs ◽  
Radiation Induced ◽  
Radix Bupleuri ◽  
Γ Rays ◽  
Induced Apoptosis ◽  
The Individual

We evaluated the effect of Bu-Zhong-Yi-Qi-Tang, a prescription of traditional Oriental medicine, and its major ingredients on protection of the intestine and hematopoietic organs against radiation damage in this study. The jejunal crypt survival, endogenous spleen colony formation, and apoptosis in jejunal crypt cells were investigated in mice irradiated with high and low doses of γ-rays. Bu-Zhong-Yi-Qi-Tang administration before irradiation protected the jejunal crypts (p < 0.0001), increased the formation of the endogenous spleen colony (p < 0.05) and reduced the frequency of radiation-induced apoptosis (p < 0.05). In experiments on the effects of the individual ingredient of Bu-Zhong-Yi-Qi-Tang, Rensan (Radix Ginseng), Danggui (Radix Angelicae gigantis), Shengma (Rhizoma Cimicifugae) and Chaihu (Radix Bupleuri) might have major radioprotective effects, and each might have different degrees of effect on these three endpoints. These results indicated that Bu-Zhong-Yi-Qi-Tang might be a better agent than any one of its ingredients to satisfy all three endpoints. Although the mechanisms of this inhibitory effect remain to be elucidated, these results indicated that Bu-Zhong-Yi-Qi-Tang might be a useful radioprotector, especially since it is a relatively non-toxic natural product. Further studies are needed to better characterize the protective nature of Bu-Zhong-Yi-Qi-Tang extract and its ingredients.

The Fanconi anemia complementation group C gene product: structural evidence of multifunctionality

Blood ◽  
2001 ◽  
Vol 98 (5) ◽  
pp. 1392-1401 ◽  
Author(s):  
Qishen Pang ◽  
Tracy A. Christianson ◽  
Winifred Keeble ◽  
Jane Diaz ◽  
Gregory R. Faulkner ◽  
...  
Keyword(s):  
Gene Product ◽  
Fanconi Anemia ◽  
Bone Marrow Failure ◽  
Interferon Γ ◽  
Complementation Group ◽  
Cytokine Signaling ◽  
Cross Linking ◽  
C Cells ◽  
Structural Elements ◽  
Ifn Γ

The Fanconi anemia (FA) group C gene product (FANCC) functions to protect cells from cytotoxic and genotoxic effects of cross-linking agents. FANCC is also required for optimal activation of STAT1 in response to cytokine and growth factors and for suppressing cytokine-induced apoptosis by modulating the activity of double-stranded RNA-dependent protein kinase. Because not all FANCC mutations affect STAT1 activation, the hypothesis was considered that cross-linker resistance function of FANCC depends on structural elements that differ from those required for the cytokine signaling functions of FANCC. Structure-function studies were designed to test this notion. Six separate alanine-substituted mutations were generated in 3 highly conserved motifs of FANCC. All mutants complemented mitomycin C (MMC) hypersensitive phenotype of FA-C cells and corrected aberrant posttranslational activation of FANCD2 in FA-C mutant cells. However, 2 of the mutants, S249A and E251A, failed to correct defective STAT1 activation. FA-C lymphoblasts carrying these 2 mutants demonstrated a defect in recruitment of STAT1 to the interferon γ (IFN-γ) receptor and GST-fusion proteins bearing S249A and E251A mutations were less efficient binding partners for STAT1 in stimulated lymphoblasts. These same mutations failed to complement the characteristic hypersensitive apoptotic responses of FA-C cells to tumor necrosis factor-α (TNF-α) and IFN-γ. Cells bearing a naturally occurring FANCC mutation (322delG) that preserves this conserved region showed normal STAT1 activation but remained hypersensitive to MMC. The conclusion is that a central highly conserved domain of FANCC is required for functional interaction with STAT1 and that structural elements required for STAT1-related functions differ from those required for genotoxic responses to cross-linking agents. Preservation of signaling capacity of cells bearing the del322G mutation may account for the reduced severity and later onset of bone marrow failure associated with this mutation.

Interferon-γ–induced apoptotic responses of Fanconi anemia group C hematopoietic progenitor cells involve caspase 8–dependent activation of caspase 3 family members

Blood ◽  
2000 ◽  
Vol 96 (13) ◽  
pp. 4204-4211
Author(s):  
R. Keaney Rathbun ◽  
Tracy A. Christianson ◽  
Gregory R. Faulkner ◽  
Gary Jones ◽  
Winifred Keeble ◽  
...  
Keyword(s):  
Cell Death ◽  
Fanconi Anemia ◽  
Caspase 3 ◽  
Family Members ◽  
Hematopoietic Progenitor Cells ◽  
Caspase 8 ◽  
C Cells ◽  
Hematopoietic Progenitor ◽  
Ifn Γ ◽  
Anemia Group

Hematopoietic progenitor cells (HPC) from mice nullizygous at the Fanconi anemia (FA) group C locus and children with Fanconi anemia group C (FA-C) are hypersensitive to interferon-gamma (IFN-γ) and tumor necrosis factor-α. This hypersensitivity results, in part, from the capacity of these cytokines to prime the fas pathway. Because fas-mediated programmed cell death in many cells involves sequential activation of specific caspases, we tested the hypothesis that programmed cell death in FA HPC involves the ordered activation of specific caspase molecules. Lysates from lymphoblasts treated with both agonistic anti-fas antibody and IFN-γ contained activated caspase 3 family members (caspases 3, 6, and 7), as well as caspase 8, whereas activation of caspases 1, 2, 4, 9, and 10 was not detected. The apoptotic effects of fas agonists in IFN-γ-treated human and murine FA-C cells were blocked when pretreated with inhibitors (ac-DEVD-cho, CP-DEVD-cho, Z-DEVD-FMK) of the caspase 3 protease. Inhibitors (ac-YVAD-cho, CP-YVAD-cho, Z-YVAD-FMK) of caspase 1 did not block apoptosis or caspase 3 activation. Treatment of FA cells with the fluoromethyl ketone tetrapeptide caspase 8 inhibitor (ac-IETD-FMK) did suppress caspase 3 activation. A 4-fold greater fraction of IFN-induced FA-C cells expressed caspase 3 than FA-C cells complemented by retroviral-mediated transfer of FANCC. Therefore fas-induced apoptosis in Fanconi anemia cells of the C type involves the activation of caspase 8, which controls activation of caspase 3 family members and one direct or indirect function of the FANCC protein is to suppress apoptotic responses to IFN-γ upstream of caspase 3 activation.

Activation of purinergic P2Y2 receptors inhibits inducible NO synthase in cultured rat mesangial cells

1998 ◽  
Vol 275 (1) ◽  
pp. F103-F110 ◽  
Author(s):  
Markus G. Mohaupt ◽  
Tina Fischer ◽  
Jörg Schwöbel ◽  
R. Bernd Sterzel ◽  
Eckhard Schulze-Lohoff
Keyword(s):  
Mesangial Cells ◽  
Critical Role ◽  
Inhibitory Effect ◽  
Interferon Γ ◽  
Glomerular Injury ◽  
Inos Protein ◽  
P2y2 Receptors ◽  
Nitrite Production ◽  
Inos Protein Expression ◽  
Ifn Γ

Cytokine-induced nitric oxide (NO) is produced on glomerular inflammation. Glomerular injury and thrombocyte aggregation result in the release of nucleotides, which may regulate induced NO synthesis in cultured rat mesangial cells (MCs). ATP (10−3 M) inhibited 24-h nitrite production induced by lipopolysaccharide (LPS, 10 μg/ml)/interferon-γ (IFN-γ, 100 U/ml) by 48.2 ± 6.3%, as well as induction of inducible NOS (iNOS) protein and mRNA. Also, coincubation with either 10−4 M of UTP, ATP, or ATPγS inhibited LPS/IFN-γ-induced nitrite production by 29.9 ± 5.8, 36.4 ± 4.3, and 50.3 ± 6.5%, respectively, indicating involvement of purinergic P2Y2 receptors. Correspondingly, cultured MCs expressed P2Y2 receptor mRNA. Agonists for other purinergic receptors [α,β-methylene-ATP, 3′- O-(4-benzoyl)-benzoyl-ATP, 2-methylthio-ATP, ADP, UDP, adenosine] were ineffective. Treatment with the protein kinase C (PKC) activator phorbol 12-myristate 13-acetate (PMA, 10−8 M) reproduced the inhibitory effect of ATP on iNOS protein expression and nitrite inhibition (by 46.6 ± 10.4%). The effect of ATP or PMA was reversed by the PKC inhibitors Ro-31-8220 (10−8 M) and 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine (10−5 M), indicating that suppression of iNOS is mediated via activation of PKC through stimulated P2Y2 receptors. In conclusion, the release of purine mediators may play a critical role for iNOS expression and synthesis of NO during glomerular inflammatory disorders.

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.

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