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Differential regulation of tumor necrosis factor-α-converting enzyme and angiotensin-converting enzyme by type I and II interferons in human normal and leukemic myeloid cells

Oncogene volume 26, pages 102–110 (2007)Cite this article

Abstract

The transmembrane metalloproteases angiotensin-converting enzyme (ACE) and tumor necrosis factor-α (TNF-α)-converting enzyme (TACE/ADAM-17) have been associated with inflammation, cancer progression and angiogenesis. Few investigations into the regulation of these enzymes by physiological stimuli have been reported. In this study, we investigated the influence of interferons (IFNs) type I (α, β) and II (γ) on ACE and TACE expression of human leukemic NB4 cells and monocytes. We assessed the expression of proteases by reverse transcriptase–polymerase chain reaction, enzyme-linked immunosorbent assay and immunofluorescence analyses. IFNγ, but not type I IFNs, upregulated membrane ACE in a dose- and time-dependency and this was reflected by the increase of ACE enzymatic activity and ACE mRNA. ACE upregulation was dependent on protein synthesis. Treatment of the interferon responsive factor 1 (IRF1)-unresponsive HepG2 cell line with IFNγ did not affect ACE expression, thus suggesting the participation of the IRF1 signaling pathway in IFNγ-mediated ACE upregulation in myeloid cells. In contrast, both types of IFNs, in a dose- and time-dependent manner, downregulated surface TACE without affecting TACE transcript. Soluble TACE was not detected in the medium of IFN-treated cells. IFNγ-mediated decrease of surface TACE in NB4 cells was reversible, and correlated with an increase in intracellular TACE, suggesting that cell surface TACE was internalized in response to IFNs. These findings, showing the presence of IFN-dependent controlled mechanisms by which ACE and TACE levels are regulated in human normal and leukemic myeloid cells, may have implications in the context of current investigations on the therapeutic potential of IFNs.

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Acknowledgements

We thank Dr M Lanotte (Hôpital Saint Louis, Paris, France) for supplying NB4 cell line, Dr B Baudin for supplying enalaprilat (Hôpital Saint-Antoine, Paris, France), Roussel-Uclaf (Romainville, France) for supplying IFNγ, Hoffman-La Roche (Basel, Switzerland) for supplying IFNα2a and Ares-Serono (Geneva, Switzerland) for supplying IFNβ. We also thank the Etablissement Français du Sang (EFS, Paris) for supplying human blood. This work was supported by grants from the Institut National de la Santé et de la Recherche Médicale and La Fondation pour La Recherche Médicale. OD was supported by the Société Française de Néphrologie and the Fondation de la Recherche médicale.

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  1. INSERM 507, Hôpital Necker, Bâtiment Lavoisier, Paris, France

    D Obeid, J Nguyen, P Lesavre & B Bauvois

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Correspondence to B Bauvois.

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Obeid, D., Nguyen, J., Lesavre, P. et al. Differential regulation of tumor necrosis factor-α-converting enzyme and angiotensin-converting enzyme by type I and II interferons in human normal and leukemic myeloid cells. Oncogene 26, 102–110 (2007). https://doi.org/10.1038/sj.onc.1209779

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