Pathophyiological and immunopharmacological studies on chemokines and their receptors

本研究旨在澄清化学品的病理学作用及其在各种疾病类型中的受体。通过这些研究，我们得到了如下结果：1）宏观炎症蛋白（MIP）-2，人类介素-8（IL-8）的功能同源物，是在体外直接在小鼠体内周期内产生的。Moreover，本地生产的MIP-2在后血管中性肺迁移进入阴道. 2）将单氯丁胺注射到大鼠体内导致的慢性脉冲高血压结合在体外宏观渗透中。Monocyte chemoattractant protein （MCP）-1是在宏观渗透的同一时间产生的。反MCP-1抗体的管理，减少了宏观渗透和允许脉冲高血压。这些结果提出，MCP-1在单细胞诱导的脉冲高血压的病理学中被引入，通过诱导宏观渗透（3）在急性类型中被引入。 ... More e的IgA神经病理学，初级IL-8级在初级MCP-1级没有增加。在对比度中，在IgA神经病的慢性类型中，它实际上发展到慢性继发性失败，而初级MCP-1水平则被标记地增加，而初级IL-8水平则不是。Moreover，我们发现了一个初级MIP-lα和MCP-1级与慢性新月形Glomerulonepritis中的新月形形成和中间部分相关的水平，相应地。因此，各种化学品在局部和不同地在患病的肾脏中产生，并为建立各种生殖器官做出了贡献。（4）血管生成和肿瘤形成通过IL-8 cDNA转染进入胃肠道癌细胞线。Moreover，我们观察到IL-8 mRNA和蛋白表达在肿瘤部位附近的非自然区域。“因为靠近坏死的区域已经成为hypoxic，我们已经将人类卵巢癌和黑色素瘤细胞线呈现为hypoxia。两种类型的转录因子激活了Hypoxia，AP-1和NF-D2 K-D2 B， thereby inducing IL-8生产。Furthermore，我们获得了关于IL-8受体在人类胃肠道癌症细胞中存在的明确证据。集体地，这些结果认为IL-8可能会被诱导血管生成和改变癌症细胞的表型的结果。5）我们观察到的C5 a激活的AP-1和NF-D2 K-D2 B，在人类单细胞线上诱导IL-8的生产.我们获得了干扰素-γ的证据，在丙酸杆菌丙烯中的粒细胞形成-初级老鼠和亚序列脂质体-诱导的活体组织损伤，通过调节宏观渗透和多种细胞因子的生产，包括肿瘤坏死因子（TNF）-α IL-12和IL-18。Less（低）

This study was performed to clarify the pathophysiological roles of chemokines and their receptors in various types of diseases. Through these studies, we obtained the results as follows.1) Macrophage inflammatory protein (MIP)-2, a functional homologue of human interleukin-8 (IL-8), was produced periodically at mouse vaginal epithelium immediately after the ovulation. Moreover, locally produced MIP-2 was involved in postovulatory neutrophil migration into vagina.2) Subcutaneous injection of monocrotaline into rats caused chronic pulmonary hypertension accompanied with intrapulmonary macrophage infiltration. Monocyte chemoattractant protein (MCP)-1 was produced at the onset of macrophage infiltration. The administration of anti-MCP-1 antibodies reduced macrophage infiltration and alleviated pulmonary hypertension. These results suggest that MCP-1 was involved in the pathogenesis of monocrotaline-induced pulmonary hypertension, through inducing macrophage infiltration.3) In an acute typ … More e of IgA nephropathy, urinary IL-8 levels were increased with no increase in urinary MCP-1 levels. In contrast, in a chronic type of IgA nephropathy which is prone to develop chronic renal failure, urinary MCP-1 levels were markedly increased while urinary IL-8 levels were not. Moreover, we found that urinary MIP-lα and MCP-1 levels correlated with crescent formation and interstitial lesions in chronic crescentic glomerulonephritis, respectively. Thus, various chemokines were produced locally and differentially at the diseased kidney, thereby contributing to the establishment of various renal lesions.4) Angiogenesis and tumor formation was enhanced by IL-8 cDNA transfection into gastric cancer cell lines. Moreover, we observed IL-8 mRNA and protein expression near necrotic areas in the tumor sites. Because the area close to necrosis is presumed to be hypoxic, we rendered human ovarian cancer and melanoma cell lines hypoxia. Hypoxia activated two types of transcription factors, AP-1 and NF-ィイD2KィエD2B, thereby inducing IL-8 production. Furthermore, we obtained definitive evidence on the presence of IL-8 receptors on human gastric cancer cells. Collectively, these results suggest that IL-8 may be involved in tumor progression by inducing angiogenesis and changing the phenotypes of cancer cells.5) We observed that C5a activated AP-1 and NF-ィイD2KィエD2B, thereby inducing IL-8 production in a human monocyte cell line.6) We obtained the evidence that interferon-γ was involved in granuloma formation in Propinibacterium acnes-primed mice and subsequent lipopolysaccharide-induced liver tissue damage, by regulating macrophage infiltration and the production of several cytokines including tumor necrosis factor (TNF)-α IL-12, and IL-18. Less