Essential role of STAT3 in the control of the acute-phase response as revealed by inducible gene activation in the liver

We generated mice carrying a STAT3 allele amenable to Cre-mediated deletion and intercrossed them with R-lx-Cre transgenic mice, in which the expressi on of Cre recombinase can be induced by type I interferon. Interferon-induc ed deletion of STAT3 occurred very efficiently (more than 90%) in the liver and slightly less efficiently (about 70%) in the bone marrow. Analysis of the induction of liver acute-phase genes in response to bacterial lipopolys accharide unequivocally identifies STAT3 as a fundamental mediator of their induction. The different degrees of defectiveness displayed by the various genes allowed us to differentiate them into three separate groups accordin g to their degree of dependence on STAT3. Induction was totally defective f or group I genes, defective at 24 h but almost normal at earlier time point s for group II. genes, and only slightly defective for group III genes. Thi s division was in good agreement with the known structures of the respectiv e promoters. We also found that the overall induction of the transcription factors C/EBP beta and -delta was only minimally defective in the absence o f STAT3. Finally, even though corticosterone levels and action were found t o be normal in the conditional-mutant mice, production of both proinflammat ory and antiinflammatory cytokines was increased and prolonged, probably as a result of STAT3 deletion in macrophages.