Study on the action mechanism of IL-1 and its regulation

IL-1在宿主反应中发挥重要作用，包括免疫、炎症和血液学反应，并在细胞增殖和分化调节中发挥重要作用。因此，阐明EL-1的作用、产生及其调控机制具有重要意义。本研究从多方面研究了IL-1的作用及其调控机制。1)IL-1信号转导。我们分析了IL-1抑制A375人黑色素瘤细胞增殖的机制。我们在CHOP下游发现了一个受p38MAPK调控的新蛋白TRB3。通过对TRB3基因启动子区域的分析，发现CHOP-ATP区域对该基因的激活具有重要作用。此外，TRB3抑制CHOP2)IL-1受体家族的转录活性。已知的Toll样受体，即IL-1家族，是细菌和合成寡核苷酸的信号分子。我们发现IL-1能增强小鼠肝细胞…中TLR2的表达和基因活性更多的卵细胞。TGFR通过下调IL-1诱导的IL-1受体I型(IL-1RI)表达，从而下调IL-1诱导的TLR2表达。转化生长因子β还抑制IL-1诱导的人成纤维细胞IL-1RI的表达。3)IL-1α的基因表达机制：A375R8细胞结构性产生IL-1α。我们发现IL-1α基因启动子的GC富集区对于构成基因的激活是重要的。此外，Sp1与GC富集区的结合以及Sp1与HDAC1的结合对于IL-1α基因的激活是重要的。雌激素通过雌激素受体a诱导人类风湿关节炎患者滑膜成纤维细胞中IL-1α启动子活性的激活。4)碳水化合物偶联IL-1：将唾液酸或唾液酸半乳糖与人IL-1α偶联。糖链偶联的IL-1α的体外活性一般表现为生物活性降低。而碳水化合物偶联的IL-1α对唾液酸具有选择性，C9臂也可与肿瘤坏死因子α偶联。碳水化合物标记的肿瘤坏死因子α对小鼠的毒性较小，但对小鼠的抗肿瘤活性较强。较少

IL-1 plays an important role in host reactions, including immunologic, inflammatory and hematologic reactions, and in regulation of cell proliferation and differentiation. Therefore, it is important to elucidate the mechanism of EL-1 action, production and its regulation. In this study we studied the many aspects of IL-1 action and its regulatory mechanisms.1) IL-1 signaling. We analyzed the mechanism of IL-1 action leading to the inhibition of cell proliferation of A375 human melanoma cells. We discovered a novel protein TRB3 in the downstream of CHOP, which is regulated by p38 MAPK By the analysis of the promoter region of TRB3 gene, CHOP-ATP region appeared to be important for the gene activation. Furthermore, TRB3 inhibited the transcriptional activity of CHOP.2) IL-1 receptor family. Toll like receptors, the IL-1 family, are known to be signaling molecule for bacteria and synthetic oligonudeotide. We found that IL-1 augments the expression and gene activation of TLR2 in mouse hepa … More tocytes. TGFR down regulated the IL-1-induced TLR2 expression by down-regulation the IL-1 induced up-regulation of IL-1 receptor type I(IL--1RI). TGFβ also inhibited the IL-1 induced IL-1RI expression in human fibroblasts.3) Gene expression mechanism of IL-1α: A375R8 cells constitutively produce IL-1α. We found that GC-rich region of the IL-1α gene promoter is important for the constitutive gene activation. Furthermore, the binding of Sp1 to the GC rich region and an association of Sp1 and HDAC1 are important for the IL-1α gene activation. Estrogen induced the activation of IL-1α promoter activity via estrogen receptor a in human rheumatoid arthritis patient-derived fibroblast like synovial cells.4) Carbohydrate conjugated IL-1: Sialic acid or sialylgalactose with C9 arm was conjugated to human IL-1α. In vitro activity of the carbohydrate-conjugated IL-1α generally exhibited the reduction in its biological activities in vitro. However, the carbohydrate-conjugated IL-1α exhibited selective activities in viva Sialic acid with C9 arm was also could be conjugated to TNFα. The carbohydrate conjugated TNFα exhibited reduced toxicity to mouse but enhanced anti-tumor activity to tumor in mice. Less