Interleukin-4 (IL-4) is a pleiotropic lymphokine which plays an important role in the immune system. IL-4 activates two distinct signalling pathways through tyrosine phosphorylation of Stat6, a signal transducer and activator of transcription, and of a 170K protein called 4PS. To investigate the functional role of Stat6 in IL-4 signalling, we generated mice deficient in Stat6 by gene targeting. We report here that in the mutant mice, expression of CD23 and major histocompatibility complex (MHC) class II in resting B cells was not enhanced in response to IL-4. IL-4 induced B-cell proliferation costimulated by anti-IgM antibody was abolished. The T-cell proliferative response was also notably reduced. Furthermore, production of Th2 cytokines from T cells as well as IgE and IgG1 responses after nematode infection were profoundly reduced. These findings agreed with those obtained in IL-4 deficient mice or using antibodies to IL-4 and the IL-4 receptor. We conclude that Stat6 plays a central role in exerting IL-4 mediated biological responses.

Signal transducer and activator of transcription (STAT) proteins have been shown to mediate biological actions in response to cytokines. Stat3, a member of the STAT family, is activated by a variety of cytokines, including the interleukin 6 family of cytokines, leptin, granulocyte colonystimulating factor, and epidermal growth factor. To address the biological function of Stat3, we generated mice deficient in Stat3 by gene targeting. No viable Stat3-deficient mice could be obtained from heterozygote intercross. Analysis of embryos at several gestation times revealed that Stat3-deficient embryos showed a rapid degeneration between embryonic days 6.5 and 7.5, although they developed into the egg cylinder stage until embryonic day 6.0. These results demonstrate that Stat3 is essential for the early development of mouse embryos.Signal transducer and activator of transcription (STAT) proteins have been shown to play an important role in cytokine signaling pathways (1, 2). These proteins are tyrosinephosphorylated by Janus kinases after cytokine binding to its receptor. Once phosphorylated, STAT proteins form homo-or heterodimers, through interaction between the Src homology 2 domain and phosphorylated tyrosine, rapidly translocate to the nucleus and induce several gene expressions. Until now, six members of STAT family, Stat1 through Stat6, have been identified. Each member is shown to be activated by its specific cytokine and responsible for cytokine-mediated responses. Recent studies from mice deficient in several STAT family members have demonstrated that STAT proteins play an essential role in cytokine-mediated biological actions; Stat1 is critical for interferon-mediated actions and innate immunity (3, 4). Stat4 is essential for interleukin (IL)-12-mediated functions and Th1 cell differentiation, whereas Stat6 is for IL-4-mediated functions and Th2 cell differentiation (5-9).Stat3 was originally identified as acute phase response factor, which is activated by IL-6 family of cytokines (10,11). This molecule is shown to be important for IL-6-mediated biological effects on cultured cell lines (12,13). Further studies have demonstrated that Stat3 is activated in response to a variety of cytokines in addition to IL-6 family of cytokines. Stat3 is shown to be tyrosine-phosphorylated by granulocyte colony-stimulating factor and epidermal growth factor (EGF) in cultured cells (11,14). Furthermore, leptin, a hormone that regulates satiety and energy metabolism, has been shown to induce the activation of Stat3 in the hypothalamus (15). To examine the biological functions of Stat3, we have generated Stat3-deficient mice. MATERIALS AND METHODSGeneration of Stat3-Deficient Mice. The Stat3 genomic DNA was screened from 129͞Sv mouse genomic library, subcloned into pBluescript SK vector (Stratagene), and characterized by restriction enzyme mapping and DNA sequencing as described (16). A targeting vector was designed to replace a 3.0-kb genomic fragment containing exons 20, 21, and 22 with the pMC1-neo (Stratagene). The ...

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