Mechanisms of IL-6 function determining growth and differentiation of lymphocytes and marophages

IL-6 功能决定淋巴细胞和巨噬细胞生长和分化的机制

基本信息

批准号：
08457105
负责人：
NAKAJIMA Koichi
金额：
$ 1.41万
依托单位：
Osaka University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1996
资助国家：
日本
起止时间：
1996 至 1997
项目状态：
已结题

项目摘要

1. We have elucidated the roles of each signaling pathways of IL-6 in a variety of cells using a series of gp130 mutant receptors and dominant-negative STA T3. The points made clear are as follows. 1) STA T3 activity is critical in IL-6-induced growth arrest and macrophage differentiation of M1 leukemic cells. STA T3 is involved in both repression of c-myc and c-myb expression and activation of junB and IRF1.2) For proliferative signals, both STA T3-mediated signals and another signals derived from the second tyrosine residue of gp130 are required in BAF/B03 cells. Especially, STA T3 provides anti-apoptotic signals. 3) In collaboration with us, Drs.Fukui and Ihara showed that Ras/MAP kinase pathway is critical in IL-6 induced neutrite outgrowth of PC12 cells which had been pretreated with NGF for 2h. Importantly, STA T3 has a negative effect on the neurite inducing activity. Consistently with this, NGF pretreatment was found to attenuate the subsequent STA T3 activation by IL-6.2. We showed that the carboxi-terminal region of STA T5 can bind to the kinase-like domain of JAK kinases and presented a model, where JAK kinases activated by IL-6 directly phosphorylate and activate STA T5 without using phsophorylated tyrosine residues of the gp130.3. We identified two other target genes for STA T3 in M1 cells. Both the p19^<INK4D> gene, a CDK inhibitor, and the stat3 gene itself are activated by STA T3. We further showed that STA T3 rapidly induced transcriptional activation of the stat3 gene through an IL-6 response element, located at -335/-314 in the stat3 gene promoter, which consists of a low-affinity STA T binding element and a CRE.Complex formation containing a STA T3 homo-dimer and an unidentified CRE-binding protein are required for full response. The autoregulatory loop is likely to be involved in the sustained activation of STA T3 observed in IL-6-stimulated M1 cells.

1。我们使用一系列GP130突变受体和显性阴性STA T3阐明了IL-6在各种细胞中的每个信号通路的作用。明确的观点如下。 1）STA T3活性在IL-6诱导的M1白血病细胞的生长停滞和巨噬细胞分化中至关重要。在BAF/B03细胞中，STA T3参与了C-MYC和C-MYB表达的抑制，以及用于增生信号的ud型信号，均与sTA T3介导的信号，以及从GP130的第二个酪氨酸残基中得出的另一个信号。特别是，STA T3提供抗凋亡信号。 3）与我们合作，Fukui和Ihara Drs.fukui和Ihara表明，RAS/MAP激酶途径在IL-6诱导的中性物质生长中至关重要，PC12细胞已用NGF预处理2H。重要的是，STA T3对神经突诱导活性具有负面影响。一致地，发现NGF预处理可通过IL-6.2衰减随后的STA T3激活。我们表明，Sta T5的羧基末端区域可以与JAK激酶的激酶样结构域结合，并提出了一个模型，其中由IL-6激活的JAK激酶直接磷酸化并激活STA T5，而无需使用GP130.3的phsophodymated酪氨酸残基而无需使用phsopheryal的酪氨酸残基。我们确定了M1细胞中STA T3的另外两个靶基因。 p19^<ink4d>基因，CDK抑制剂和STAT3基因本身均被STA T3激活。 We further showed that STA T3 rapidly induced transcriptional activation of the stat3 gene through an IL-6 response element, located at -335/-314 in the stat3 gene promoter, which consists of a low-affinity STA T binding element and a CRE.Complex formation containing a STA T3 homo-dimer and an unidentified CRE-binding protein are required for full response.自动调节环可能与在IL-6刺激的M1细胞中观察到的STA T3的持续激活有关。