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

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