Interferon-alpha inhibits cell cycle progression by Ba/F3 cells through the antagonisation of interleukin-3 effects on key regulators of G(1)/S transition

The molecular mechanisms of interferon-alpha (IFN-alpha)-mediated cell growth inhibition are incompletely understood. Here, we have analysed how IFN-alpha interferes with the interleukin-3 (IL-3)-stimulated cell cycle progression by Ba/F3 cells. The antiproliferative cytokine caused a delay in cell cycle progression, which correlated with a diminished activation of the cyclin-dependent kinases 2 and 4 in IL-3-stimulated cells. While IFN-alpha did not affect the expression of p27(Kip1) and p21(Waf1), it efficiently inhibited the IL-3-induced expression of D-type cyclin and cyclin E proteins. No IL-3-antagonistic effects of the IFN, however, were observed at the mRNA level of cyclin expression. Furthermore, IFN-alpha suppressed the IL-3-induced release of E2F transcription factors from the retinoblastoma protein (pRb) and enhanced pRb-mediated transcriptional repression. The growth factor-antagonistic action of IFN-alpha correlated with a strong stimulation of protein kinase R expression, suggesting that inhibition of protein synthesis plays a pivotal role in IFN-alpha-mediated inhibition of cell cycle progression.