Characterization of the mouse IFN-lambda ligand-receptor system: IFN-lambdas exhibit antitumor activity against B16 melanoma.
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.
Lasfar
Ahmed
A
Department of Biochemistry and Molecular Biology, University of Medicine and Dentistry-New Jersey Medical School, Newark, New Jersey 07103, USA.
Lewis-Antes
Anita
A
Smirnov
Sergey V
SV
Anantha
Shubha
S
Abushahba
Walid
W
Tian
Bin
B
Reuhl
Kenneth
K
Dickensheets
Harold
H
Sheikh
Faruk
F
Donnelly
Raymond P
RP
Raveche
Elizabeth
E
Kotenko
Sergei V
SV
D000595:Amino Acid Sequence; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D003001:Cloning, Molecular; D006224:Cricetinae; D005260:Female; D006801:Humans; D007372:Interferons / Q000235:genetics / Q000276:immunology*; D008024:Ligands; D008546:Melanoma, Experimental / Q000235:genetics / Q000276:immunology* / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D017471:Receptors, Interferon / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction; D014162:Transfection
D008024:Ligands; D017471:Receptors, Interferon; D007372:Interferons