Signal transducer and activator of transcription 3 (STAT3) is the main mediator of interleukin 6 (IL-6)-type cytokine signaling. It exists in two isoforms: the full-length STAT3 alpha and the truncated STAT3 beta, generally thought to act as a dominant negative factor. To assess their relative functions, we ablated the expression of either isoform by gene targeting. We show here that in vivo STAT3 beta is not a dominant negative factor. Its expression can rescue the embryonic lethality of a STAT3-null mutation and it can by itself induce the expression of specific STAT3 target genes. Nevertheless, STAT3 alpha has nonredundant roles such as modulation of cellular responses to IL-6 and mediation of IL-10 function in macrophages.

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SOCS-3 (suppressor of cytokine signaling 3) is an intracellular protein that is selectively and rapidly induced by appropriate agonists and that modulates responses of immune cells to cytokines by interfering with the Janus kinase/signal transducer and activator of transcription (Jak/STAT) pathway. On the basis of the observations that interferon ␥ (IFN␥) up-regulates SOCS-3 gene and protein expression in primary mouse macrophages, J774 macrophage cell line and embryonal fibroblasts, we investigated which sequences of the 5 SOCS-3 gene are responsive to IFN␥. By promoter deletion analysis we identified a functional IFN␥-responsive element, located at nucleotides ؊72/؊64 upstream from the transcription initiation, whose presence and integrity is necessary to ensure responsiveness to IFN␥. This element contains a STAT consensus binding sequence (SOCS-3/STAT-binding element (SBE)) whose specific mutation totally abolished the responsiveness to IFN␥. In contrast, discrete deletion of other 5 regions of the SOCS-3 promoter did not substantially modify the inducibility by IFN␥. Electromobility shift assay analyses revealed that IFN␥ promotes specific DNA binding activities to an oligonucleotide probe containing the SOCS-3/SBE sequence. Even though IFN␥ triggered tyrosine phosphorylation of both STAT1 and STAT3 in macrophages and J774 cells, only STAT1 was appropriately activated and thus found to specifically bind to the SOCS-3/SBE oligonucleotide probe. Accordingly, IFN␥-induced SOCS-3 protein expression was not impaired in STAT3-deficient embryonal fibroblasts. Taken together, these results demonstrate that the induction of SOCS-3 by IFN␥ depends upon the presence of a STAT-binding element in the SOCS-3 promoter that is specifically activated by STAT1.

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