Type III interferon induces apoptosis in human lung cancer cells.

The apoptotic effects of interferon lambdas (IFN lambda s) have been described in several types of cancers. However, their effects on human lung cancer cells and the mechanisms are elusive. In addition, the interaction between IFN lambda s and other interferons remains unclear. The interplay between IFN alpha and IFN lambda has been reported. However, although IFN gamma is a well-known regulatory interferon, the mechanisms through which it regulates IFN lambda s in lung cancer cells are unknown. These issues are critical for the application of IFN lambda s in lung cancer therapy. In this study, we used A549, a cell line derived from a human lung carcinoma, to characterize the antiproliferative and apoptotic effects of IFN lambda s on lung cancer, and the interplay between IFN gamma and IFN lambda. Because overexpression of full-length ectopic IFN lambda R1 led to cell death, we generated A549 cells stably expressing a chimeric receptor (10R1/lambda R1), which is composed of the extracellular domain of IL-10 receptor (IL10R1) fused in tandem to the transmembrane and intracellular domains of the IFN lambda receptor (IFN lambda R1). By comparing with A549 cells stably expressing its cognate vector, we demonstrated that IL-10 stimulation triggered the intracellular IFN lambda signaling via 10R1/lambda R1 receptor. By using A549 cells expressing 10R1/lambda R1, we report that the IFN lambda R1 chain of IFN lambda receptor possesses an intrinsic ability to trigger apoptosis in human lung cancer cells. Although it did not suppress cell proliferation, IFN lambda signaling via 10R1/lambda R1 receptor induced cell cycle arrest, externalization of phosphatidylserine, DNA fragmentation, activation of caspase-3, caspase-8 and caspase-9. However, the caspase inhibitor Z-VAD-FMK did not prevent apoptosis. In addition, the extent of induced apoptosis correlate with the expression levels of the IFN lambda receptor and the levels of STAT1 activation. Lastly, we demonstrated that IFN gamma sensitized A549 cells to IFN lambda-induced apoptosis, via upregulation of IFN lambda R1. These data indicate the potential of IFN lambda, alone or in combination with IFN gamma, in the treatment of human lung carcinoma.