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

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.