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

Abstract

Interleukin-1b (IL-1b) 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-1b is not believed to induce tumor cell death. Here we demonstrate that prolonged treatment with IL-1b, in combination with interferon-c (IFNc), is cytotoxic for L929 tumor cells. IL-1b/IFNc-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-1b/IFNc. Cell death in response to IL-1b/IFNc is independent of caspases, but requires the IL-1b/IFNc-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 IjB kinase b inhibitor. Altogether, these findings demonstrate that prolonged exposure to IL-1b plus IFNc induces L929 tumor cell necrosis, via a p38MAPK and nuclear factorjB (NF-jB)-dependent signaling pathway, leading to the expression of iNOS and the production of toxic NO levels.

Interferon Regulatory Factor (IRF)-1 Is a Master Regulator of the Cross Talk between Macrophages and L929 Fibrosarcoma Cells for Nitric Oxide Dependent Tumoricidal Activity

“…In line with our observations with TNFα treatment and NO production, it was shown that L929 tumor cells treated with a combination of IFNγ and IL-1 displayed a significant increase in NO production and cell death indicating that L929 cells do produce NO that, in turn, depending on the concentration, has an autocrine cytotoxic effect [ 17 ]. Interestingly, using macrophages from iNOS deficient mice in the co-cultures with L929 cells, we verified that although low, NO production persisted, suggesting that, in our experimental conditions, L929 cells might also release this metabolite.…”

“…L929 murine fibrosarcoma cell line treated with Actinomycin D (ActD), a transcription inhibitor, becomes extremely susceptible to TNFα induced cytotoxicity [ 14 , 15 ], where TNFα treatment promotes ROS production prior to cell death [ 16 ]. However, in absence of ActD, treatment with IL-1β and IFNγ induces cytotoxicity in L929 cells, via the p38/NFκB/iNOS/NO pathway [ 17 ]. In this case, IRF-1 is an element of convergence of these pathways, once, as described before, it is central for IFN signalling, but also may be expressed upon p65 NFκB binding to its promoter.…”

Neuroinflammation mediated by IL-1β increases susceptibility of dopamine neurons to degeneration in an animal model of Parkinson's disease

“…Sites of overlap include, phospholipid hydrolysis and protein tyrosine kinase phosphorylation in the cell and shared nuclear binding motifs, κB and NF-IL6 [ 62 - 65 ]. All three cytokines share the transcription factor Nf-κB, a key regulator of pro-inflammatory cytokine expression [ 66 - 68 ]. IL-1ra administration therefore may not have only attenuated cell loss through blockade of IL-1 signaling per se, but also these data suggest that regulation of other cytokines (TNF-α and IFN-γ) likely also contributed.…”

A model for cancer-suppressive inflammation

“…Mice with established subcutaneous MCA-106 sarcoma tumors were cured by the combinatorial treatment with TNFα and IL-6, revealing a synergistic antitumor effect of these two pro-inflammatory cytokines 59 . In vitro studies demonstrated that a combination of IFNγ and IL-1β induced necrosis of murine L929 fibrosarcoma cells 94 . Combined treatment of human papillary thyroid carcinoma cell lines with IL-1β and IFNγ efficiently inhibited proliferation and invasiveness 95 .…”