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C/EBPβ is required for 'emergency' granulopoiesis

Nature Immunology volume 7, pages 732–739 (2006)Cite this article

Abstract

During 'emergency' situations such as infections, host defense requires rapid mobilization of bone marrow granulocyte progenitors. 'Steady-state' granulopoiesis is absolutely dependent on the C/EBPα transcription factor, but the transcriptional mechanisms underlying emergency granulopoiesis remain unclear. Here we show that large numbers of granulocytes were generated from C/EBPα-deficient progenitors after cytokine stimulation in vivo. Cytokine treatment or fungal infection induced upregulation of C/EBPβ but not C/EBPα or C/EBPε transcripts in granulocyte progenitors, and C/EBPβ-deficient progenitors showed decreased emergency-induced granulopoiesis in vitro and in vivo. C/EBPβ inhibited proliferation less severely than did C/EBPα. These data suggest a critical function for C/EBPβ in emergency granulopoiesis, which demands both differentiation and proliferation of granulocyte precursors.

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Figure 1: Granulopoiesis induced by hydrodynamics-mediated gene transfer of cytokine expression vectors.
Figure 2: Cytokine influence on myeloid progenitors.
Figure 3: 'Rescue' of granulopoiesis in Cebpa−/− mice.
Figure 4: C/EBPβ in cytokine-induced proliferation and differentiation of granulocytes.
Figure 5: C/EBPβ in granulopoiesis induced by fungal infection.
Figure 6: C/EBPα-independent granulopoiesis is mediated by C/EBPβ.
Figure 7: Analyses of K562 cell lines stably expressing the fusion protein C/EBPαER or C/EBPβER or the estrogen receptor hormone-binding domain alone (ER).

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Acknowledgements

We thank S. Elf, M.E. Guiney and K. Martens for assistance in animal husbandry; J. Yang and R. Hanson for assistance in procuring Cebpb−/− mice; L. Prickett for cell sorting; and G. Huang, S. Kobayashi, A. Kawasaki, D.A. Gonzalez, H. Iwasaki and all other members of the laboratories of D.G.T. and K.A. for discussions and suggestions. Supported by the National Institutes of Health (HL56745 to D.G.T.).

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Authors and Affiliations

  1. Harvard Institutes of Medicine and Harvard Stem Cell Institute, Boston, 02115, Massachusetts, USA

    Hideyo Hirai, Pu Zhang, Tajhal Dayaram, Christopher J Hetherington & Daniel G Tenen

  2. Department of Microbiology, Kyoto Prefectural University of Medicine, Kyoto, Japan

    Hideyo Hirai & Jiro Imanishi

  3. Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Harvard Medical School, Boston, 02115, Massachusetts, USA

    Shin-ichi Mizuno & Koichi Akashi

  4. Center for Cellular and Molecular Medicine, Kyushu University Hospital, Fukuoka, 812-0034, Japan

    Koichi Akashi

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Supplementary information

Supplementary Fig. 1

Serum cytokine concentrations after hydrodynamics-mediated gene transfer (PDF 88 kb)

Supplementary Fig. 2

Functional analysis of BM progenitors with or without cytokine treatment in vivo. (PDF 42 kb)

Supplementary Fig. 3

Rescue of granulopoiesis in Cebpaf/f conditional knockout mice by cytokine treatments. (PDF 97 kb)

Supplementary Fig. 4

Cebpb−/− progenitors demonstrate reduced proliferative potential in vitro (PDF 653 kb)

Supplementary Fig. 5

K562 cell lines stably expressing ER proteins fused to C/EBPα or C/EBPβ. (PDF 869 kb)

Supplementary Fig. 6

Effects of C/EBPα and C/EBPβ on cell cycle status of BAF and 32D cell lines (PDF 459 kb)

Supplementary Table 1

Differential counts of methylcellulose colony assay. (PDF 49 kb)

Supplementary Table 2

Primers and probes for quantitative PCR. (PDF 76 kb)

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Hirai, H., Zhang, P., Dayaram, T. et al. C/EBPβ is required for 'emergency' granulopoiesis. Nat Immunol 7, 732–739 (2006). https://doi.org/10.1038/ni1354

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