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Inflammatory reactions and severe neutropenia in mice lacking the transcriptional repressor Gfi1

Nature Genetics volume 30, pages 295–300 (2002)Cite this article

Abstract

The transcriptional repressor Gfi1 is a nuclear zinc-finger protein expressed in T-cell precursors in the thymus and in activated mature T lymphocytes1,2,3,4. Previous experiments have shown that Gfi1 is involved in T-cell lymphomagenesis and in the development of T-cell progenitors5,6,7. Here we show that Gfi1 is also expressed outside the lymphoid system in granulocytes and activated macrophages, cells that mediate innate immunity (that is, non-specific immunity). We have generated Gfi1-deficient mice (Gfi1−/−) and show that these animals are severely neutropenic and accumulate immature monocytic cells in blood and bone marrow. Their myeloid precursor cells are unable to differentiate into granulocytes upon stimulation with granulocyte colony–stimulating factor (G-CSF) but can develop into mature macrophages. We found that Gfi1−/− macrophages produce enhanced levels of inflammatory cytokines, such as tumor necrosis factor (TNF), interleukin-10 (IL-10) and IL-1β, when stimulated with bacterial lipopolysaccharide (LPS) and that Gfi1−/− mice succumb to low doses of this endotoxin that are tolerated by wildtype mice. We conclude that Gfi1 influences the differentiation of myeloid precursors into granulocytes or monocytes and acts in limiting the inflammatory immune response.

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Figure 1: Expression pattern and targeted disruption of Gfi1.
Figure 2: Gfi1−/− mice show severe neutropenia and accumulation of immature myeloid cells.
Figure 3: Analysis of peripheral blood and hematopoietic precursors of Gfi1-deficient mice.
Figure 4: Histopathology and cytokine levels in Gfi1−/− mice.

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Acknowledgements

We thank P. Ferrier, Marseille, for the pPNT vector and Rag1-deficient mice, and A. Nagy, Toronto, for R1 ES cells. We are indebted to I. Spratte, W. Wegrzyn and E. Gau for excellent technical assistance, K. Lennartz for FACS assistance and P. Plessow and T. Civela for animal care. This work was supported by the Deutsche Forschungsgemeinschaft, DFG, the Fonds der chemischen Industrie, the European Community Framework 5 Program and the IFORES Program of the University of Essen Medical School.

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Author notes

  1. Thorsten Schmidt

    Present address: Bayer AG, Apratherweg 18a, D-42096, Wuppertal, Germany

  2. Branko Zevnik

    Present address: Artemis Pharmaceuticals GmbH, Neurather Ring 1, D-51063, Köln, Germany

Authors and Affiliations

  1. Institut für Zellbiologie (Tumorforschung), IFZ, Universitätsklinikum Essen, Essen, D-45122, Germany

    Holger Karsunky, Hui Zeng, Thorsten Schmidt, Branko Zevnik & Tarik Möröy

  2. Institut für Versuchstierkunde, RWTH Aachen, Aachen, D-52074, Germany

    Reinhart Kluge

  3. Institut für Pathologie, Universitätsklinikum Essen, Essen, D-45122, Germany

    Kurt Werner Schmid

  4. Abteilung für Hämatologie, Universitätsklinikum Essen, Essen, D-45122, Germany

    Ulrich Dührsen

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  1. Holger Karsunky
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Correspondence to Tarik Möröy.

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Karsunky, H., Zeng, H., Schmidt, T. et al. Inflammatory reactions and severe neutropenia in mice lacking the transcriptional repressor Gfi1. Nat Genet 30, 295–300 (2002). https://doi.org/10.1038/ng831

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