Prolonged exposure to IL-1beta and IFNgamma induces necrosis of L929 tumor cells via a p38MAPK/NF-kappaB/NO-dependent mechanism

Oncogene. 2008 Jun 19;27(27):3780-8. doi: 10.1038/onc.2008.4. Epub 2008 Feb 4.


Interleukin-1beta (IL-1beta) 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-1beta is not believed to induce tumor cell death. Here we demonstrate that prolonged treatment with IL-1beta, in combination with interferon-gamma (IFNgamma), is cytotoxic for L929 tumor cells. IL-1beta/IFNgamma-induced cytotoxicity requires only minimal amounts of IL-1beta 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-1beta/IFNgamma. Cell death in response to IL-1beta/IFNgamma is independent of caspases, but requires the IL-1beta/IFNgamma-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 IkappaB kinase beta inhibitor. Altogether, these findings demonstrate that prolonged exposure to IL-1beta plus IFNgamma induces L929 tumor cell necrosis, via a p38MAPK and nuclear factor-kappaB (NF-kappaB)-dependent signaling pathway, leading to the expression of iNOS and the production of toxic NO levels.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Death / drug effects
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Interferon-gamma / toxicity*
  • Interleukin-1beta / toxicity*
  • Mice
  • NF-kappa B / metabolism*
  • Necrosis
  • Nitric Oxide / metabolism*
  • Tumor Necrosis Factor-alpha / toxicity
  • p38 Mitogen-Activated Protein Kinases / metabolism*


  • Interleukin-1beta
  • NF-kappa B
  • Tumor Necrosis Factor-alpha
  • Nitric Oxide
  • Interferon-gamma
  • p38 Mitogen-Activated Protein Kinases