IFN-gamma impairs release of IL-8 by IL-1beta-stimulated A549 lung carcinoma cells

BMC Cancer. 2008 Sep 18;8:265. doi: 10.1186/1471-2407-8-265.

Abstract

Background: Production of interferon (IFN)-gamma is key to efficient anti-tumor immunity. The present study was set out to investigate effects of IFNgamma 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)-1beta alone or in combination with IFNgamma. 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 Balpha, cellular IL-8, and cyclooxygenase-2 was analyzed by Western blot analysis.

Results: Here we demonstrate that IFNgamma efficiently reduced IL-8 secretion under the influence of IL-1beta. Surprisingly, real-time PCR analysis and RPA revealed that the inhibitory effect of IFNgamma on IL-8 was not associated with significant changes in mRNA levels. These observations concurred with lack of a modulatory activity of IFNgamma on IL-1beta-induced NF-kappaB activation as assessed by cellular IkappaB levels. Moreover, analysis of intracellular IL-8 suggests that IFNgamma modulated IL-8 secretion by action on the posttranslational level. In contrast to IL-8, IL-1beta-induced cyclooxygenase-2 expression and release of IL-6 were not affected by IFNgamma indicating that modulation of IL-1beta action by this cytokine displays specificity.

Conclusion: Data presented herein agree with an angiostatic role of IFNgamma as seen in rodent models of solid tumors and suggest that increasing T helper type 1 (Th1)-like functions in lung cancer patients e.g. by local delivery of IFNgamma may mediate therapeutic benefit via mechanisms that potentially include modulation of pro-angiogenic IL-8.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Cyclooxygenase 2 / biosynthesis
  • Enzyme-Linked Immunosorbent Assay
  • Humans
  • I-kappa B Proteins / metabolism
  • Interferon-gamma / immunology*
  • Interleukin-1beta / antagonists & inhibitors
  • Interleukin-1beta / pharmacology
  • Interleukin-6 / immunology
  • Interleukin-8 / biosynthesis
  • Interleukin-8 / genetics
  • Interleukin-8 / immunology*
  • Lung Neoplasms / blood supply
  • Lung Neoplasms / genetics
  • Lung Neoplasms / immunology*
  • Neovascularization, Pathologic / immunology
  • RNA, Messenger / biosynthesis
  • RNA, Messenger / genetics

Substances

  • I-kappa B Proteins
  • Interleukin-1beta
  • Interleukin-6
  • Interleukin-8
  • RNA, Messenger
  • Interferon-gamma
  • Cyclooxygenase 2