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Prolonged exposure to IL-1β and IFNγ induces necrosis of L929 tumor cells via a p38MAPK/NF-κB/NO-dependent mechanism

Oncogene volume 27, pages 3780–3788 (2008)Cite this article

Abstract

Interleukin-1β (IL-1β) is a cytokine that shares with tumor necrosis factor (TNF) the ability to initiate largely similar signaling pathways, leading to proinflammatory gene expression. In contrast to TNF, however, IL-1β is not believed to induce tumor cell death. Here we demonstrate that prolonged treatment with IL-1β, in combination with interferon-γ (IFNγ), is cytotoxic for L929 tumor cells. IL-1β/IFNγ-induced cytotoxicity requires only minimal amounts of IL-1β and shows morphological features of necrosis. Although TNF induces a similar response, we could exclude a contribution of endogenous TNF production in the effect of IL-1β/IFNγ. Cell death in response to IL-1β/IFNγ is independent of caspases, but requires the IL-1β/IFNγ-induced production of inducible nitric oxide synthase (iNOS) and NO. Moreover, necrosis and iNOS/NO production could be prevented by treatment of the cells with a p38 mitogen activated protein kinase (p38MAPK) or IκB kinase β inhibitor. Altogether, these findings demonstrate that prolonged exposure to IL-1β plus IFNγ induces L929 tumor cell necrosis, via a p38MAPK and nuclear factor-κB (NF-κB)-dependent signaling pathway, leading to the expression of iNOS and the production of toxic NO levels.

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Acknowledgements

We thank Meeus and W Burm for their technical assistance with cell culture work. This work was supported in part by grants from the ‘Interuniversitaire Attractiepolen’ (IAP6/18), the ‘Fonds voor Wetenschappelijk Onderzoek-Vlaanderen’ (FWO; grant 3G010505), and the ‘Geconcerteerde Onderzoeksacties’ of the University of Ghent (GOA; grant 01G06B6). EV and PS were respectively supported as a predoctoral research fellow and a postdoctoral research associate with the FWO. LV holds a predoctoral fellowship from the ‘Vlaams Instituut voor de Bevordering van het Wetenschappelijk-technologisch Onderzoek in de Industrie’ (IWT).

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  1. Department for Molecular Biomedical Research, Unit of Molecular Signal Transduction in Inflammation, VIB, Ghent, Belgium

    E Vercammen, J Staal, A Van Den Broeke, M Haegman, L Vereecke, P Schotte & R Beyaert

  2. Department of Molecular Biology, Ghent University, Ghent, Belgium

    E Vercammen, J Staal, A Van Den Broeke, M Haegman, L Vereecke, P Schotte & R Beyaert

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  1. E Vercammen
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Correspondence to R Beyaert.

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

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Vercammen, E., Staal, J., Van Den Broeke, A. et al. Prolonged exposure to IL-1β and IFNγ induces necrosis of L929 tumor cells via a p38MAPK/NF-κB/NO-dependent mechanism. Oncogene 27, 3780–3788 (2008). https://doi.org/10.1038/onc.2008.4

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