Differences in nuclear signaling by leukemia inhibitory factor and interferon-gamma: the role of STAT proteins in regulating vasoactive intestinal peptide gene expression.

To investigate the importance of STAT protein activation in leukemia inhibitory factor (LIF)-mediated induction of neuropeptide gene transcription, we compared signaling to the 180-bp cytokine response element (CyRE) in the vasoactive intestinal peptide (VIP) promoter by interferon-gamma (IFN-gamma) and LIF. We show that LIF and IFN-gamma activate STAT proteins but only LIF activates VIP gene transcription. Thus STAT activation is not sufficient for VIP transcriptional activation. In a CyRE reporter plasmid, in which the STAT site has been deleted, LIF, but not IFN-gamma, activates transcription, indicating that sequences within the CyRE distinct from the STAT site are important to LIF-mediated transcriptional activation. The CyRE does not mediate transcriptional activation to LIF in a non-VIPergic cell line, suggesting that cell-specific factors exist which are permissive for cytokine-dependent regulation of gene expression. Human and mouse sequences are highly conserved in the region of the CyRE, consistent with the functional importance of multiple regions of the CyRE. These findings show that regions within the CyRE distinct from the STAT site are important to the LIF-dependent regulation of VIP gene expression and enable the CyRE to respond in a cell-specific and cytokine-specific manner.