Pleiotropic functions of cytokines and STAT5

我们一直在利用STAT5的组成型活性突变体研究细胞因子多效性功能的分子机制（Onishi等）。分子生物学杂志，1998；Ariyoshi等人。J Biol Chem, 2000)，我们通过pcr驱动的随机诱变，然后逆转录病毒介导的表达筛选来鉴定。STAT5是一种已知的转录因子，可诱导多种靶基因的表达。我们之前已经证明STAT5可以分别通过诱导pim-1、p21和SOCS1在相同的细胞中诱导增殖、分化和凋亡（Nosaka et al, EMBO J, 1999）。我们现在已经确定了一种新的机制，通过这种机制，组成活性STAT5诱导M1细胞的巨噬细胞分化；活性STAT5通过分泌IL-6诱导巨噬细胞分化（Kawashima等）。免疫学杂志，2001)。有趣的是，IL-6基因的启动子不包含STAT5的结合位点，活性STAT5诱导IL-6是通过激活NFkB介导的。现在我们正在研究潜在的分子机制，初步结果表明STAT5激活诱导的分泌蛋白负责IL-6的产生（Nakamura等）。生物化学学报，2002)。这种分泌蛋白的鉴定目前正在进行中。

We have been working on molecular mechanisms of the pleiotropic functions of cytokines using the constitutively active mutants of STAT5 (Onishi et al. Mol Cell Biol, 1998; Ariyoshi et al. J Biol Chem, 2000) which we identified by PCR-driven random mutagenesis followed by retrovirus-mediated expression screening. STAT5 is a transcription factor known to induce the expression of a variety of target genes. We previously demonstrated that STAT5 could induce proliferation, differentiation, and apoptosis in the same cells through induction of pim-1, p21 and SOCS1, respectively (Nosaka et al, EMBO J, 1999). We have now identified a novel mechanism by which the constitutively active STAT5 induced macrophage differentiation of M1 cells ; the active STAT5 induced macrophage differentiation via autocrine production of IL-6 (Kawashima et al. J Immunol, 2001). Interestingly, the promoter of the IL-6 gene does not contain the biding site of STAT5, and the induction of IL-6 by the active STAT5 was mediated through activation of NFkB. Now we are investigating the underlying molecular mechanism, and the preliminary results indicate that a secreted protein induced by STAT5 activation is responsible for IL-6 production (Nakamura et al. J Biol Chem, 2002). The identification of this secreted protein is now ongoing.