Modulation of the activation of Stat1 by the interferon-γ receptor complex

The activation of Stat1 by the interferon-gamma (IFN-γ) receptor complex is responsible for the transcription of a significant portion of IFN-γ induced genes. Many of these genes are responsible for the induction of an apoptotic state in response to IFN-γ. In the absence of Stat1 activation, IFN-γ instead induces a proliferative response. Modifying Stat1 activation by IFN-γ may have pharmacological benefits. We report that the rate of activation of Stat1 can be altered in HeLa cells by overexpressing either the IFN-γR1 chain or the IFN-γR2 chain. These alterations occur in hematopoietic cell lines: Raji cells and monocytic cell lines, which have average and above-average IFN-γR2 surface expression, activate Stat1 similarly to HeLa cells and HeLa cells overexpressing IFNγR2, respectively. The rapid Stat1 activation seen in HeLa cells can be inhibited by overexpressing a chimeric IFN-γR2 chain that does not bind Jak2 or (when high concentrations of IFN-γ are used) by overexpressing IFN-γR1. These data are consistent with a model in which the recruitment of additional Jak2 activity to a signaling complex accelerates the rate of Stat1 activation. We conclude that the rate of activation of Stat1 in cells by IFN-γ can be modified by regulating either receptor chain and speculate that pharmacological agents which modify receptor chain expression may alter IFN-γ receptor signal transduction.