LAUSR

Significance We describe unexpected cooperation between two cytokines that are important in regulating the growth of cancers, namely, type I interferons (IFNs) and interleukin 6 (IL6). It is well established that IL6 is vital for the ability of many tumor types to prosper, and the work in the current paper reveals that the signaling pathway driven by IFN, which is also evident in many cancers, increases the expression of IL6 through a direct effect on the IL6 gene. The findings may help to identify new antitumor targets for therapy. In response to IFNβ, the IL6 gene is activated, modestly at early times by ISGF3 (IRF9 plus tyrosine-phosphorylated STATs 1 and 2), and strongly at late times by U-ISGF3 (IRF9 plus U-STATs 1 and 2, lacking tyrosine phosphorylation). A classical IFN-stimulated response element (ISRE) at −1,513 to −1,526 in the human IL6 promoter is required. Pretreating cells with IFNβ or increasing the expression of U-STAT2 and IRF9 exogenously greatly enhances IL6 expression in response to the classical NF-κB activators IL1, TNF, and LPS. U-STAT2 binds tightly to IRF9, the DNA binding subunit of ISGF3, and also to the p65 subunit of NF-κB. Therefore, as shown by ChIP analyses, U-STAT2 can bridge the ISRE and κB elements in the IL6 promoter. In some cancer cells, the protumorigenic activation of STAT3 will be enhanced by the increased synthesis of IL6 that is facilitated by high expression of U-STAT2 and IRF9.