Regulation of apoptosis by type III interferons

Objective: Two types of interferons (IFNs), type I (IFN-alpha/beta) and type III (IFN-lambda s), utilize distinct receptor complexes to induce similar signalling and biological activities, including recently demonstrated for IFN-lambda s antitumour activity. However, ability of type III IFNs to regulate cell population growth remains largely uncharacterized.Materials and methods: Intact and modified human colorectal adenocarcinoma HT29 cells were used to study regulation of apoptosis by IFN-lambda s. Results and Conclusions: We report that the IFN-lambda R1 chain of the type III IFN receptor complex possesses an intrinsic ability to trigger apoptosis in cells. Signalling induced through the intracellular domain of IFN-lambda R1 resulted in G(1)/G(0) phase cell cycle arrest, phosphatidylserine surfacing and chromosomal DNA fragmentation. Caspase-3, caspase-8 and caspase-9 were activated; however, pancaspase inhibitor Z-VAD-FMK did not prevent apoptosis. In addition, the extent of apoptosis correlated with the level of receptor expression and was associated with prolonged IFN-lambda signalling. We also demonstrated that the ability to trigger apoptosis is a unique intrinsic function of all IFN receptors. However, more robust apoptosis was induced by signalling through type III IFN receptor than through type I or type II (IFN-gamma) receptors, suggesting higher cytotoxic potential of type III IFNs. In addition, we observed that IFN-gamma treatment sensitized HT29 cells to IFN-lambda-mediated apoptosis. These results provide evidence that type III IFNs, alone or in combination with other stimuli, have the potential to induce apoptosis.