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Characterization of the mouse IFN-lambda ligand-receptor system: IFN-lambdas exhibit antitumor activity against B16 melanoma.

Abstract
Recently discovered type III IFNs (IFN-lambda) exert their antiviral and immunomodulatory activities through a unique receptor complex composed of IFN-lambdaR1 and interleukin-10 receptor 2. To further study type III IFNs, we cloned and characterized mouse IFN-lambda ligand-receptor system. We showed that, similar to their human orthologues, mIFN-lambda2 and mIFN-lambda3 signal through the IFN-lambda receptor complex, activate IFN stimulated gene factor 3, and are capable of inducing antiviral protection and MHC class I antigen expression in several cell types including B16 melanoma cells. We then used the murine B16 melanoma model to investigate the potential antitumor activities of IFN-lambdas. We developed B16 cells constitutively expressing murine IFN-lambda2 (B16.IFN-lambda2 cells) and evaluated their tumorigenicity in syngeneic C57BL/6 mice. Although constitutive expression of mIFN-lambda2 in melanoma cells did not affect their proliferation in vitro, the growth of B16.IFN-lambda2 cells, when injected s.c. into mice, was either retarded or completely prevented. We found that rejection of the modified tumor cells correlated with their level of IFN-lambda2 expression. We then developed IFN-lambda-resistant B16.IFN-lambda2 cells (B16.IFN-lambda2Res cells) and showed that their tumorigenicity was also highly impaired or completely abolished similar to B16.IFN-lambda2 cells, suggesting that IFN-lambdas engage host mechanisms to inhibit melanoma growth. These in vivo experiments show the antitumor activities of IFN-lambdas and suggest their strong therapeutic potential.
AuthorsAhmed Lasfar, Anita Lewis-Antes, Sergey V Smirnov, Shubha Anantha, Walid Abushahba, Bin Tian, Kenneth Reuhl, Harold Dickensheets, Faruk Sheikh, Raymond P Donnelly, Elizabeth Raveche, Sergei V Kotenko
JournalCancer research (Cancer Res) Vol. 66 Issue 8 Pg. 4468-77 (Apr 15 2006) ISSN: 0008-5472 [Print] United States
PMID16618774 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • Ligands
  • Receptors, Interferon
  • Interferons
Topics
  • Amino Acid Sequence
  • Animals
  • COS Cells
  • Chlorocebus aethiops
  • Cloning, Molecular
  • Cricetinae
  • Female
  • Humans
  • Interferons (genetics, immunology)
  • Ligands
  • Melanoma, Experimental (genetics, immunology, therapy)
  • Mice
  • Mice, Inbred C57BL
  • Molecular Sequence Data
  • Receptors, Interferon (genetics, immunology)
  • Signal Transduction
  • Transfection

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