IFN-α and IFN-λ differ in their antiproliferative effects and duration of JAK/STAT signaling activity

Abstract

Interferon (IFN)-λ, also known as IL-28A, IL-28B or IL-29, is a new type III IFN, which like type I IFN-(α/β), activates common elements of the JAK/STAT signaling pathway and exhibits antiproliferative activity. Currently, IFN-α is used in the treatment of certain forms of cancer, but its antitumor effects are limited and associated with high toxicity. In this study, we determined whether IFN-λ induced the same level of cell growth inhibition relative to IFN-α. To this effect HaCaT cells, which are typically growth inhibited by IFN-α, underwent apoptosis in response to IFN-λ. Next, in contrast to IFN-α stimulation, IFN-λ prolonged the duration of activated STAT1 and STAT2. Furthermore, the kinetics of IFN-stimulated genes was different as IFN-λ induced a delayed but stronger induction of IFN-responsive genes. Components of the JAK/STAT pathway remained essential for the antiproliferative effects of IFN-α and IFN-λ. IFN-λ-induced persistence of STAT activation required de novo protein synthesis and was in part due to a delay in STAT2 inactivation. Thus our data demonstrate that the duration of IFN-λ signaling is different from that of IFN-α, and that IFN-λ could be a suitable cytokine to evaluate for cancer therapy.