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Hematopoietic cells from gadd45a-deficient and gadd45b-deficient mice exhibit impaired stress responses to acute stimulation with cytokines, myeloablation and inflammation

Oncogene volume 25, pages 5537–5546 (2006)Cite this article

Abstract

The gadd45 family of gene(s) is rapidly induced by genotoxic stress or by differentiation-inducing cytokines. Using bone marrow (BM) from gadd45a−/−, gadd45b−/− and wild-type (wt) mice, we investigated their role in stress responses of myeloid cells to acute stimulation with differentiating cytokines, myelotoxic agents and inflammatory substances. Bone marrow cells from gadd45a−/− and gadd45b−/− mice displayed compromised myeloid differentiation and higher apoptosis in vitro, following acute stimulation with a variety of differentiating cytokines. Intriguingly, gadd45a−/− and gadd45b−/− colony forming units granulocyte/macrophage progenitors displayed prolonged proliferation capacity compared to wt controls upon re-plating in methylcellulose supplemented with interleukin-3. The recovery of the BM myeloid compartment following 5-Fluorouracil-induced myelo-ablation was much slower in gadd45a−/− and gadd45b−/− mice compared to wt controls. Furthermore, the response of myeloid cells to inflammatory stress, inflicted via intraperitoneal administration of sodium caseinate was impaired in gadd45a−/− and gadd45b−/− mice compared to age-matched wt mice, as indicated by lower percentage of Gr-1-positive cells in the BM and lower number of myeloid cells in peritoneal exudates. Overall, these data indicate that both gadd45a and gadd45b play a role in modulating physiological stress responses of myeloid cells to acute stimulation with differentiating cytokines, myelo-ablation and inflammation. These findings should aid in understanding the response of normal and malignant hematopoietic cells to physiological and chemical stressors including anticancer agents.

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Acknowledgements

We thank Dr Albert Fornace Jr for the Gadd45a−/− mice. This work was supported by RO1 HL70530-03 (DL).

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  1. Department of Biochemistry, Fels Institute for Cancer Research & Molecular Biology, Temple University School of Medicine, Philadelphia, PA, USA

    S K Gupta, M Gupta, B Hoffman & D A Liebermann

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  1. S K Gupta
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  2. M Gupta
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  3. B Hoffman
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  4. D A Liebermann
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Correspondence to D A Liebermann.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

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Gupta, S., Gupta, M., Hoffman, B. et al. Hematopoietic cells from gadd45a-deficient and gadd45b-deficient mice exhibit impaired stress responses to acute stimulation with cytokines, myeloablation and inflammation. Oncogene 25, 5537–5546 (2006). https://doi.org/10.1038/sj.onc.1209555

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