Boost, Kim A.; Sadik, Christian D.; Bachmann, Malte; Zwissler, Bernhard; Pfeilschifter, Josef; Muehl, Heiko:
IFN-gamma impairs release of IL-8 by IL-1 beta-stimulated A549 lung carcinoma cells.
In: BMC Cancer
Background: Production of interferon (IFN)-gamma is key to efficient anti-tumor immunity. The present study was set out to investigate effects of IFN. on the release of the potent pro-angiogenic mediator IL-8 by human A549 lung carcinoma cells. Methods: A549 cells were cultured and stimulated with interleukin (IL)-1 beta alone or in combination with IFN gamma. IL-8 production by these cells was analyzed with enzyme linked immuno sorbent assay (ELISA). mRNA-expression was analyzed by real-time PCR and RNase protection assay (RPA), respectively. Expression of inhibitor-kappa B alpha, cellular IL-8, and cyclooxygenase-2 was analyzed by Western blot analysis. Results: Here we demonstrate that IFN gamma efficiently reduced IL-8 secretion under the influence of IL-1 beta. Surprisingly, real-time PCR analysis and RPA revealed that the inhibitory effect of IFN gamma on IL-8 was not associated with significant changes in mRNA levels. These observations concurred with lack of a modulatory activity of IFN gamma on IL-1 beta-induced NF-kappa B activation as assessed by cellular I kappa B levels. Moreover, analysis of intracellular IL-8 suggests that IFN gamma modulated IL-8 secretion by action on the posttranslational level. In contrast to IL-8, IL-1 beta-induced cyclooxygenase-2 expression and release of IL-6 were not affected by IFN gamma indicating that modulation of IL-1 beta action by this cytokine displays specificity. Conclusion: Data presented herein agree with an angiostatic role of IFN gamma as seen in rodent models of solid tumors and suggest that increasing T helper type I (Th1)-like functions in lung cancer patients e.g. by local delivery of IFN gamma may mediate therapeutic benefit via mechanisms that potentially include modulation of pro-angiogenic IL-8.