IFN-γ-mediated hematopoietic cell destruction in murine models of immune-mediated bone marrow failure
Open accessAbstract
Interferon gamma (IFN-γ) has been reported to have both negative and positive activity on hematopoietic cells, adding complexity to the interpretation of its pleiotropic functions. We examined the effects of IFN-γ on murine hematopoietic stem cells (HSCs) and progenitors in vitro and in vivo by using mouse models. IFN-γ treatment expanded bone marrow (BM) c-Kit(+)Sca1(+)Lin(-) (KSL) cell number but reduced BM KLCD150(+) and KLCD150(+)CD48(-) cells. IFN-γ-expanded KSL cells engrafted poorly when tested by competitive repopulation in vivo. KSL, KLCD150(+), and KLCD150(+)CD48(-) cells from IFN-γ-treated animals all showed significant upregulation in Fas expression. When cocultured with activated T cells in vitro, KSL and KLCD150(+) cells from IFN-γ-treated donors showed increased apoptosis relative to those from untreated animals, and infusion of activated CD8 T cells into IFN-γ-injected animals in vivo led to partial elimination of KSL cells. Exposure of BM cells or KSL cells to IFN-γ increased expression of Fas, caspases, and related proapoptotic genes and decreased expression of Ets-1 and other hematopoietic genes. In mouse models of BM failure, mice genetically deficient in IFN-γ receptor expression showed attenuation of immune-mediated marrow destruction, whereas effector lymphocytes from IFN-γ-deficient donors were much less potent in initiating BM damage. We conclude that the activity of IFN-γ on murine hematopoiesis is context dependent. IFN-γ-augmented apoptotic gene expression facilitates destruction of HSCs and progenitors in the presence of activated cytotoxic T cells, as occurs in human BM failure.
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IFN-g can directly affect HSCs: STAT1 signaling leads to cycling and differentiation, ultimately resulting in stem cell exhaustion, whereas upregulation of SOCS1 blocks self-renewing capacities.
“IFN-g can directly affect HSCs: STAT1 signaling leads to cycling and differentiation, ultimately resulting in stem cell exhaustion, whereas upregulation of SOCS1 blocks the self-renewing capacities.56”
From Inflammatory bone marrow microenvironment (2019) · cites this paper as [56]
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- Authors
- Chen, J., Feng, X., Desierto, M. J., Keyvanfar, K., & Young, N. S.
- Affiliations
- National Institutes of Health (US)
- Venue
- Blood
- Publisher
- American Society of Hematology
- Published
- 2015-12-10
- Volume
- 126
- Issue
- 24
- Pages
- 2621-2631
- ISSN
- 0006-4971 (ISSN-L)
- 1528-0020
- PMC
- PMC4671109
- OpenAlex
- W2333387353
- Cited by
- 97
- References
- 74
- Citations by year
- 2026: 9 · 2025: 10 · 2024: 8 · 2023: 8 · 2022: 8 · 2021: 12 · 2020: 13 · 2019: 8 · 2018: 12 · 2017: 6 · 2016: 3
- FWCI
- 5.49
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Blood (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- Topics
- Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Blood disorders and treatments
- Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
- Keywords
- interferon-gamma, immune-mediated bone marrow failure, hematopoietic stem cells, hematopoietic progenitor cells, apoptosis, Fas, cytotoxic T lymphocytes, KSL cells, competitive repopulation, ETS1, caspases, hematopoiesis
- MeSH terms
- Bone Marrow Failure Disorders, Interferon gamma Receptor, Anemia, Aplastic, Animals, Bone Marrow Diseases, Cells, Cultured, Colony-Forming Units Assay, Disease Models, Animal, Gene Expression Regulation, Hematopoiesis, Hematopoietic Stem Cells, Hemoglobinuria, Paroxysmal, Interferon-gamma, Mice, Inbred C57BL, T-Lymphocytes, Cytotoxic, Bone Marrow Transplantation, Apoptosis, Receptors, Interferon, Coculture Techniques, fas Receptor, Mice, Congenic, Mice, Fas Ligand Protein
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