Prolonged exposure to IL-1beta and IFNgamma induces necrosis of L929 tumor cells via a p38MAPK/NF-kappaB/NO-dependent mechanism.
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.
Vercammen
E
E
Unit of Molecular Signal Transduction in Inflammation, Department for Molecular Biomedical Research, VIB, Ghent, Belgium.
Staal
J
J
Van Den Broeke
A
A
Haegman
M
M
Vereecke
L
L
Schotte
P
P
Beyaert
R
R
D000818:Animals; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D007371:Interferon-gamma / Q000633:toxicity*; D053583:Interleukin-1beta / Q000633:toxicity*; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D009336:Necrosis; D009569:Nitric Oxide / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000633:toxicity; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D053583:Interleukin-1beta; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D007371:Interferon-gamma; D048051:p38 Mitogen-Activated Protein Kinases