scholarly journals Impact of interferon-γ on hematopoiesis

Blood ◽  
2014 ◽  
Vol 124 (16) ◽  
pp. 2479-2486 ◽  
Author(s):  
Alexander M. de Bruin ◽  
Carlijn Voermans ◽  
Martijn A. Nolte
Keyword(s):  
Interferon Γ ◽  
Cytokine Signaling ◽  
Tumor Control ◽  
Strong Impact ◽  
Hematopoietic Stem ◽  
Physiological Processes ◽  
Ifn Γ ◽  
Novel Concept ◽  
Intracellular Infections ◽  
The Impact

Abstract The proinflammatory cytokine interferon-γ (IFN-γ) is well known for its important role in innate and adaptive immunity against intracellular infections and for tumor control. Yet, it has become clear that IFN-γ also has a strong impact on bone marrow (BM) output during inflammation, as it affects the differentiation of most hematopoietic progenitor cells. Here, we review the impact of IFN-γ on hematopoiesis, including the function of hematopoietic stem cells (HSCs) and more downstream progenitors. We discuss which hematopoietic lineages are functionally modulated by IFN-γ and through which underlying molecular mechanism(s). We propose the novel concept that IFN-γ acts through upregulation of suppressor of cytokine signaling molecules, which impairs signaling of several cytokine receptors. IFN-γ has also gained clinical interest from different angles, and we discuss how chronic IFN-γ production can lead to the development of anemia and BM failure and how it is involved in malignant hematopoiesis. Overall, this review illustrates the wide-ranging effect of IFN-γ on the (patho-)physiological processes in the BM.

scholarly journals Eltrombopag maintains human hematopoietic stem and progenitor cells under inflammatory conditions mediated by IFN-γ

Blood ◽  
2019 ◽  
Vol 133 (19) ◽  
pp. 2043-2055 ◽  
Author(s):  
Luigi J. Alvarado ◽  
Heather D. Huntsman ◽  
Hai Cheng ◽  
Danielle M. Townsley ◽  
Thomas Winkler ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Binding Site ◽  
Bone Marrow Failure ◽  
Interferon Γ ◽  
General Mechanism ◽  
Clinical Activity ◽  
Critical Pathway ◽  
Hematopoietic Stem ◽  
Therapeutic Implications ◽  
Ifn Γ

Abstract The proinflammatory cytokine interferon-γ (IFN-γ) has been implicated in human hematopoietic stem and progenitor cell (HSPC) depletion in immune-mediated bone marrow failure syndromes. We show that IFN-γ specifically prevents full engagement of thrombopoietin (TPO), a primary positive regulator of HSPC survival, to its receptor (c-MPL) via steric occlusion of the low-affinity binding site, contributing to perturbation of TPO-induced signaling pathways and decreased survival of human HSPCs. Eltrombopag, a synthetic small molecule mimetic of TPO that interacts with c-MPL at a position distinct from the extracellular binding site of TPO, bypasses this inhibition, providing an explanation for its clinical activity in bone marrow failure, despite already elevated endogenous TPO levels. Thus, IFN-γ–mediated perturbation of TPO:c-MPL complex formation and the resulting inhibition of a critical pathway of growth factor cell signaling may represent a general mechanism by which IFN-γ impairs the function of human HSPCs. This understanding could have broad therapeutic implications for various disorders of chronic inflammation.

Investigation of TCR-Vβ CDR3 Spectrotypes in CD4 and CD8 Lymphocytes from Paroxysmal Nocturnal Hemoglobinuria (PNH) Patients.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2827-2827
Author(s):  
Akiko Nakamura ◽  
Tsutomu Shichishima ◽  
Hideyoshi Noji ◽  
Kazuhiko Ikeda ◽  
Yukio Maruyama
Keyword(s):  
Bone Marrow ◽  
Healthy Volunteer ◽  
Bone Marrow Failure ◽  
Interferon Γ ◽  
Relative Increase ◽  
Hematopoietic Stem ◽  
Bone Marrow Failure Syndromes ◽  
Abnormal Cells ◽  
Ifn Γ ◽  
Cd4 Lymphocytes

Abstract PNH is one disorder of bone marrow failure syndromes, including aplastic anemia and myelodysplastic syndrome. It is considered that immunologic mechanisms by cytotoxic T lymphocytes (CTLs) and interferon-γ (IFN-γ) contribute to hypoplastic bone marrow of these disorders. In addition, PNH is an acquired clonal disorder of the hematopoietic stem cell. Recently, it has been reported that analysis of T cell-antigen receptor (TCR)-Vβ repertoires, especially TCR-Vβ CDR3 (complementarity- determining region 3) spectrotypes, is an effective tool to study immunologic mechanisms by CTLs in pathophysiology of PNH (Karadimitris et al, Blood, 2000; Kook et al, Blood, 2002; Risitano et al, Blood, 2002). In the present study, we investigated 21 kinds of TCR-Vβ repertoires by flow cytometry in CD4 and CD8 lymphocytes from 5 PNH patients and a healthy volunteer and the TCR-Vβ CDR3 spectrotypes using polymerase chain reaction assay in CD4 and CD8 lymphocytes from 3 of 5 PNH patients and the control. We also quantitated intracellular IFN-γ in CD4 and CD8 lymphocytes from 5 PNH patients and the control according to the method by Sloand et al (Blood, 2002). We found no specific TCR-Vβ repertoires in CD4 and CD8 lymphocytes from PNH patients compared with the control. The TCR-Vβ repertoires with relative increase of CD4 or CD8 lymphocytes (over 10 of ratio of the proportion of each TCR-Vβ repertoire in a PNH patient/the proportion of the same TCR-Vβ repertoire in a healthy volunteer) were 13.6 or 4 and 22 in Case 1, 3 and 11 or 1 in Case 2, 3 and 13.6 or 3 in Case 3, 5.3 and 7.2 or 2, 3, 7, and 18 in Case 4, and 4, 5.2, 13.6, 16, and 23 or 1 and 14 in Case 5, respectively. TCR-Vβ CDR3 spectrotyping showed that in CD4 lymphocytes most CDR3 patterns were chiefly polyclonal, except for one oligoclonal (Case 1) and one monoclonal (Case 3) patterns of TCR-Vβ25; in CD8 lymphocytes most CDR3 consisted of polyclonal, oligoclonal, and/or monoclonal patterns, suggesting the possibility that CD8 lymphocytes recognize much more antigens of abnormal cells, probably including PNH clones, than CD4 lymphocytes. Unfortunately, we found the same patterns as described above in CD8 lymphocytes from the control, although CD4 lymphocytes from the control presented only polyclonal pattern of CDR3. Quantitative analyses of IFN-γ showed that index values of IFN-γ in CD4 and CD8 lymphocytes from PNH patients were higher than those from the control. However, we did not find any significant correlations between the spectrotypes of TCR-Vβ CDR3 and the index values of IFN-γ in PNH patients, suggesting that TCR-Vβ repertoires with monoclonal and oligoclonal CDR3 patterns do not necessarily produce much IFN-γ. In conclusion, our findings suggest that TCR-Vβ CDR3 spectrotyping is more effective tool to resolve some immune mechanisms of pathophysiology in PNH, especially by auto-reactive CTLs.

Interferon-Gamma Impairs Expansion and Hematopoietic Support of Bone Marrow Mesenchymal Stromal Cells

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3884-3884
Author(s):  
Marieke Goedhart ◽  
Anne Cornelissen ◽  
Carlijn Kuijk ◽  
Sulima Geerman ◽  
Fernanda Pascutti ◽  
...  
Keyword(s):  
Stromal Cells ◽  
Stromal Compartment ◽  
Self Renewal ◽  
Hematopoietic Stem ◽  
Ifn Γ ◽  
Immunomodulatory Properties ◽  
Pre Treatment ◽  
The Impact

Abstract Maintenance of hematopoietic stem cells (HSCs) and regulation of their quiescence and self-renewal is critical for maintaining a lifelong supply of blood cells. The ability of HSCs to stay quiescent is thought to depend on their specific niche in the bone marrow (BM). Mesenchymal stromal cells (MSC) in the BM are multipotent stem cells that form part of the vascular HSC niche and provide micro-environmental support to HSCs both in vivo and upon expansion ex vivo. Culture-expanded MSCs also exhibit immunomodulatory properties that can be enhanced by pre-treatment with interferon-gamma (IFN-γ). BM MSC are thus attractive candidates for cellular therapy after hematopoietic stem cell transplantation, for promoting rapid hematopoietic recovery and reducing the incidence or severity of graft versus host disease. Although IFN-γ pre-treatment can improve the immunomodulatory properties of MSCs, elevated IFN-γ levels have also been associated with anemia and BM failure in multiple chronic inflammatory diseases. While the impact of IFN-γ on HSC has been elucidated in recent years, it remains largely unknown whether IFN-γ can also influence hematopoietic support by BM stromal cells. In this study, we aim to elucidate the impact of IFN-γ on hematopoietic support of BM MSC. We show that in vitro expansion of primary BM MSC cultures from healthy donors was significantly reduced in the presence of IFN-γ, and this effect could be reproduced in the BM stromal cell line MS-5. Concurrently, IFN-γ diminished the clonal capacity of BM MSC, as measured by CFU-F assays. In addition, BM MSC that were pre-stimulated with IFN-γ produced significantly lower levels of CXCL12, suggesting a loss of hematopoietic support potential. Indeed, support of CD34+ hematopoietic stem and progenitor cells (HSPC) in a co-culture assay was greatly reduced in when MSC were pre-treated with IFN-γ. To determine the impact of IFN-γ on BM MSC in vivo, we investigated the BM stromal compartment of IFN-γ AU-rich element deleted (ARE-Del) mice, which constitutively express IFN-γ in steady state conditions. FACS analysis revealed a remodeling of the BM stromal compartment in ARE-Del mice compared to littermate controls, with significantly fewer MSCs, identified as CD45-Ter119-CD31-CD51+PDGFRa+ cells. Numbers of other stromal cell subsets, such as osteoblasts and fibroblasts, were not altered. The reduction of BM MSC in ARE-Del mice coincided with a loss of quiescence in HSCs; only 35% of long term HSC (LT-HSC) in ARE-Del mice were quiescent, compared to 70% in WT mice, as determined by Ki-67 staining. Loss of quiescence in LT-HSC did not lead to increased self-renewal, but rather induced increased differentiation towards short-term HSC and multi-potent progenitors. We then sorted LT-HSC from WT and ARE-Del mice and performed in vitro HSC culture assays in the absence of IFN-γ. Absolute numbers of LT-HSC were rapidly decreased in ARE-Del compared to WT cultures after 3 and 7 days of HSC culture, while numbers of more differentiated progenitors were increased. These data indicate that an IFN-γ-mediated loss of BM MSC in ARE-Del mice leads to loss of quiescent LT-HSCs and induces a tendency towards HSC differentiation over self-renewal. In conclusion, we have shown that IFN-γ has a negative impact on expansion and hematopoietic support of BM MSC in vitro and in vivo across species. Although IFN-γ treatment enhances the immunomodulatory function of MSCs in a clinical setting, it is obvious from our data that IFN-γ impairs their HSC supporting function. These data also provide more insight in the underlying mechanism by which IFN-γ contributes to the pathogenesis of anemia and BM failure. Disclosures No relevant conflicts of interest to declare.

scholarly journals Checks and balances between human cytomegalovirus replication and indoleamine-2,3-dioxygenase

2014 ◽  
Vol 95 (3) ◽  
pp. 659-670 ◽  
Author(s):  
Albert Zimmermann ◽  
Sebastian Hauka ◽  
Marco Maywald ◽  
Vu Thuy Khanh Le ◽  
Silvia K. Schmidt ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Human Cytomegalovirus ◽  
Cell Types ◽  
Interferon Γ ◽  
Counter Measures ◽  
Indoleamine 2,3 Dioxygenase ◽  
Infected Cells ◽  
Hcmv Replication ◽  
Ifn Γ ◽  
The Impact

Despite a rigorous blockade of interferon-γ (IFN-γ) signalling in infected fibroblasts as a mechanism of immune evasion by human cytomegalovirus (HCMV), IFN-γ induced indoleamine-2,3-dioxygenase (IDO) has been proposed to represent the major antiviral restriction factor limiting HCMV replication in epithelial cells. Here we show that HCMV efficiently blocks transcription of IFN-γ-induced IDO mRNA both in infected fibroblasts and epithelial cells even in the presence of a preexisting IFN-induced antiviral state. This interference results in severe suppression of IDO bioactivity in HCMV-infected cells and restoration of vigorous HCMV replication. Depletion of IDO expression nonetheless substantially alleviated the antiviral impact of IFN-γ treatment in both cell types. These findings highlight the effectiveness of this IFN-γ induced effector gene in restricting HCMV productivity, but also the impact of viral counter-measures.

PIAS proteins promote SUMO-1 conjugation to STAT1

Blood ◽  
2003 ◽  
Vol 102 (9) ◽  
pp. 3311-3313 ◽  
Author(s):  
Daniela Ungureanu ◽  
Sari Vanhatupa ◽  
Noora Kotaja ◽  
Jie Yang ◽  
Saara Aittomäki ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Posttranslational Modifications ◽  
Interferon Γ ◽  
Regulatory Function ◽  
Cytokine Signaling ◽  
Signal Transducer ◽  
Protein Inhibitor ◽  
Ifn Γ

AbstractSignal transducer and activator of transcription 1 (STAT1) is a critical mediator of interferon-γ (IFN-γ)–induced transcription that is regulated through posttranslational modifications and through transacting proteins such as protein inhibitor of activated STAT1 (PIAS1). PIAS proteins have been shown to function as E3-type small ubiquitin-like modifier (SUMO) ligases, and sumoylation has been identified as a modulatory mechanism for several transcription factors. Here we show that STAT1 is subject to SUMO-1 modification, and sumoylation occurs in vivo and in vitro at a single, evolutionary conserved amino acid residue Lys703. Members of the PIAS family of proteins were found to strongly stimulate sumoylation of STAT1. Furthermore, activation of STAT1 by IFN-γ or pervanadate induced SUMO-1 conjugation. Mutation of Lys703 in STAT1 resulted in increased IFN-γ–mediated transactivation, suggesting a negative regulatory function for sumoylation. These results indicate that STAT1 is covalently modified by SUMO-1 in cytokine signaling and that PIAS proteins promote SUMO-1 conjugation to STAT1.

Graft-versus-host disease causes failure of donor hematopoiesis and lymphopoiesis in interferon-γ receptor-deficient hosts

Blood ◽  
2008 ◽  
Vol 112 (5) ◽  
pp. 2111-2119 ◽  
Author(s):  
Jean-Sébastien Delisle ◽  
Louis Gaboury ◽  
Marie-Pier Bélanger ◽  
Éliane Tassé ◽  
Hideo Yagita ◽  
...  
Keyword(s):  
Graft Versus Host Disease ◽  
Hematopoietic Cells ◽  
Interferon Γ ◽  
Host Cells ◽  
Type I ◽  
Host Disease ◽  
Graft Versus Host ◽  
Donor Cells ◽  
Ifn Γ ◽  
The Impact

Abstract The immunopathologic condition known as graft-versus-host disease (GVHD) results from a type I T-cell process. However, a prototypical type I cytokine, interferon-γ (IFN-γ), can protect against several manifestations of GVHD in recipients of major histocompatibility complex (MHC)–mismatched hematopoietic cells. We transplanted hematopoietic cells from C3H.SW donors in wild-type (wt) and IFN-γ-receptor–deficient (IFN-γRKO) MHC-matched C57BL/6 recipients. In IFN-γRKO recipients, host cells were unresponsive to IFN-γ, whereas wt donor cells were exposed to exceptionally high levels of IFN-γ. From an IFN-γ perspective, we could therefore evaluate the impact of a loss-of-function on host cells and gain-of-function on donor cells. We found that lack of IFN-γR prevented up-regulation of MHC proteins on host cells but did not mitigate damage to most target organs. Two salient phenotypes in IFN-γRKO recipients involved donor cells: lymphoid hypoplasia and hematopoietic failure. Lymphopenia was due to FasL-induced apoptosis and decreased cell proliferation. Bone marrow aplasia resulted from a decreased proliferation of hematopoietic stem/progenitor cells that was associated with down-regulation of 2 genes negatively regulated by IFN-γ: Ccnd1 and Myc. We conclude that IFN-γ produced by alloreactive T cells may entail a severe graft-versus-graft reaction and could be responsible for cytopenias that are frequently observed in subjects with GVHD.

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.

Intracellular interferon-γ in circulating and marrow T cells detected by flow cytometry and the response to immunosuppressive therapy in patients with aplastic anemia

Blood ◽  
2002 ◽  
Vol 100 (4) ◽  
pp. 1185-1191 ◽  
Author(s):  
Elaine Sloand ◽  
Sonnie Kim ◽  
Jaroslaw P. Maciejewski ◽  
John Tisdale ◽  
Dean Follmann ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
T Cells ◽  
Aplastic Anemia ◽  
Immunosuppressive Therapy ◽  
Immunosuppressive Treatment ◽  
Interferon Γ ◽  
Immunosuppressive Drugs ◽  
Hematopoietic Stem ◽  
Transfusion Independence ◽  
Ifn Γ

Immunosuppressive therapy leads to meaningful hematologic improvement in most patients with aplastic anemia (AA). Failure to respond and a later relapse could be due to deficient numbers of hematopoietic stem cells, inadequate treatment of the immune process, or a nonimmunologic etiology. Interferon-γ (IFN-γ) has been implicated in the pathophysiology of hematopoietic failure in AA. On the basis of previous findings showing overexpression of IFN-γ in bone marrow (BM) and peripheral blood (PB) in this disease, we hypothesized that quantitation of IFN-γ might be applied to predict and monitor responses to immunosuppressive therapy. We measured expression of IFN-γ in lymphocytes obtained from 123 AA patients, using intracellular 2-color fluorescent staining and flow cytometry. Of 70 patients with severe AA, 36 (51%) demonstrated increased IFN-γ in circulating T cells. IFN-γ was detected in only 4 of 53 patients who had recovered from AA. IFN-γ was not found in PB lymphocytes of patients with other hematologic diseases and heavy transfusion burdens or in healthy volunteers. Among 62 AA patients who were assessed before first treatment with immunosuppressive drugs, 27 of 28 (96%) with circulating IFN-γ–containing T cells subsequently responded to therapy; in contrast, only 11 of 34 (32%) patients whose PB lacked IFN-γ lymphocytes improved to transfusion independence. IFN-γ–containing lymphocytes declined following treatment in all cases. Of 17 patients assessed during relapse, IFN-γ was present in T cells prior to the blood count decline in 13, and 12 responded to reinstitution of immunosuppressive drugs. Of 30 BMs tested prior to first treatment, 20, all in responding patients, were positive for IFN-γ, whereas the negative tests were obtained in 10 nonresponding patients. IFN-γ is increased in the PB lymphocytes of many patients with AA, and these cells decline with therapy. The presence of intracellular IFN-γ may predict response to immunosuppressive treatment and also the onset of relapse.

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