Interleukin-6-Specific Activation of the C/Ebp-Delta Gene in Hepatocytes Is Mediated By Stat3 and Sp1

C/EBP delta (CCAAT/enhancer binding protein delta) has been implicated as a regulator of acute-phase response (APR) genes in hepatocytes. Its expression increases dramatically in liver during the APR and can be induced in hepatic sell lines by interleukin-6 (IL-6), an acute-phase mediator that activates transcription of many APR genes, Here we have investigated the mechanism by which C/EBP delta expression is regulated by IL-6 in hepatoma cells, C/EBP delta promoter sequences to -125 bp are sufficient for IL-6 inducibility of a reporter gene and include apt APR element (APRE) that is essential for PL-Ci responsiveness, DNA binding experiments and transactivation assays demonstrate that Stat3, but mot Stat1, interacts with this APRE. Two Spl sites, one of which is adjacent to the APRE, are required for Ik-e induction and transactivation by Stat3. Thus, Stall and Spl function cooperatively to activate the C/EBP delta promoter. Replacement of the APRE with Stat binding elements (SBEs) from the ICAM-1 or C/EBP beta promoter, both of which recognize both Stat1 and Stat3, confers responsiveness to gamma interferon, a cytokine that selectively activates Stat1. Sequence comparisons suggest that the distinct Stat binding specificities of the C/EBP delta and C/EBP beta SBEs are determined primarily by a single base pair difference. Our findings indicate that the cytokine specificity of C/EBP delta gene expression is governed by the APRE sequence. [References: 55]

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