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Tissue inhibitor of matrix metalloproteinase-1 overexpression in M1 myeloblasts impairs IL-6-induced differentiation

Oncogene volume 23, pages 9212–9219 (2004)Cite this article

Abstract

The balance between matrix metalloproteinase (MMP) and tissue inhibitor of matrix metalloproteinase (TIMP) is important for extracellular matrix interactions of hematopoietic cells. MMP-independent growth modulating activity for TIMP-1 on B lymphocytes and erythroid progenitors has also been described, but a role for TIMP-1 in myelomonocytic differentiation has not been previously reported. In this study, we demonstrate that TIMP-1 overexpression impairs differentiation of the myeloblastic M1 cell line following interleukin (IL)-6 stimulation. We generated retroviral vectors coexpressing human TIMP-1 and the green fluorescent protein (GFP) and stably transduced murine M1 myeloid cells. TIMP-1 expressing cells showed a large reduction in IL-6-induced macrophage differentiation in vitro that was reversible with a specific monoclonal antibody. The differentiation delay in M1/TIMP-1 cells was also specifically reversible by pharmacologic phosphatidylinositol-3 kinase (PI3-K) inhibition. Additionally, overexpression of a TIMP-1/GFP fusion protein also impaired M1 differentiation and this protein was localized to the cell surface, consistent with an autocrine receptor-mediated mechanism. Surprisingly, TIMP-1 transduced cells had a selective advantage for growth in IL-6, indicating that functional effects on growth and differentiation of M1 cells were primarily through an autocrine mechanism. Intrinsic TIMP-1 expression in myeloid leukemia cells might thus impact upon survival or differentiation.

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Abbreviations

TIMP:

tissue inhibitor of matrix metalloproteinase

MMP:

matrix metalloproteinase

STAT:

signal transducer and activator of transcription

GFP:

green fluorescent protein

EPA:

erythroid potentiating activity

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Acknowledgements

We thank Janna Metzler, Albert Forero, Sheikha Tschand, and Arjun Shah for technical assistance. We thank James Darnell (The Rockefeller University) for providing the wild-type STAT3 cDNA and Benjamin Glick (University of Chicago) for providing the DsRed cDNA. This work was supported by NIHR01DK059380, NIHR21HL071171, NIHR01HL073738, and the Lauri Strauss Leukemia Foundation (to KD Bunting).

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Author notes

  1. Peter Haviernik and Carisa Lahoda: These authors contributed equally to this study

Authors and Affiliations

  1. Hematopoiesis Department, American Red Cross, Jerome H Holland Laboratory for the Biomedical Sciences, Rockville, 20855, MD, USA

    Peter Haviernik, Carisa Lahoda, Heath L Bradley, Teresa S Hawley, Ali Ramezani, Robert G Hawley & Kevin D Bunting

  2. Genetics Program, The George Washington University Institute for the Biomedical Sciences, Washington, 20037, DC, USA

    Carisa Lahoda & Kevin D Bunting

  3. Flow Cytometry Facility, American Red Cross, Jerome H Holland Laboratory for the Biomedical Sciences, Rockville, 20855, MD, USA

    Teresa S Hawley

  4. Department of Anatomy and Cell Biology, The George Washington University, Washington, 20037, DC, USA

    Robert G Hawley & Kevin D Bunting

  5. Blood and Cell Therapy Development, American Red Cross, Jerome H Holland Laboratory for the Biomedical Sciences, 20855, MD, USA

    Robert G Hawley

  6. Division of Clinical Sciences, Flow Cytometry Unit, Laboratory of Pathology, National Institutes of Health, Bethesda, 20892, MD, USA

    Maryalice Stetler-Stevenson

  7. Division of Clinical Sciences, Extracellular Matrix Section, Laboratory of Pathology, National Institutes of Health, Bethesda, 20892, MD, USA

    William G Stetler-Stevenson

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  1. Peter Haviernik
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Correspondence to Kevin D Bunting.

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Haviernik, P., Lahoda, C., Bradley, H. et al. Tissue inhibitor of matrix metalloproteinase-1 overexpression in M1 myeloblasts impairs IL-6-induced differentiation. Oncogene 23, 9212–9219 (2004). https://doi.org/10.1038/sj.onc.1208096

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