Suppression of STAT5 functions in liver, mammary glands, and T cells in cytokine-inducible SH2-containing protein 1 transgenic mice

Various cytokines utilize Janus kinase (JAK) and the STAT (signal transduce rs and activators of transcription) family of transcription factors to carr y out their biological functions. Among STATs, two highly related proteins, STAT5a and STAT5b, are activated by various cytokines, including prolactin , growth hormone, erythropoietin, interleukin 2 (IL-2), and IL-3. We have c loned a STAT5-dependent immediate early cytokine-responsive gene, CIS1 (enc oding cytokine-inducible SH2-containing protein 1). In this study, we creat ed CIS1 transgenic mice under the control of a beta-actin promoter. The tra nsgenic mice developed normally; however, their body weight was lower than that of the wild-type mice, suggesting a defect in growth hormone signaling . Female transgenic mice failed to lactate after parturition because of a f ailure in terminal differentiation of the mammary glands, suggesting a defe ct in prolactin signaling. The IL-2 dependent upregulation of the IL-2 rece ptor alpha chain and proliferation were partially suppressed in the T cells of transgenic mice. These phenotypes remarkably resembled those found in S TAT5a and/or STAT5b knockout mice. Indeed, STAT5 tyrosine phosphorylation w as suppressed in mammary glands and the liver. Furthermore, the IL-2-induce d activation of STAT5 was markedly inhibited in T cells in transgenic mice, while leukemia inhibitory factor-induced STAT3 phosphorylation was not aff ected. We also found that the numbers of gamma delta T cells, as well as th ose of natural killer (NK) cells and NKT cells, were dramatically decreased and that Th1/Th2 differentiation was altered in transgenic mice. These dat a suggest that CIS1 functions as a specific negative regulator of STAT5 in vivo and plays an important regulatory role in the liver, mammary glands, a nd T cells.