Pathophyiological and immunopharmacological studies on chemokines and their receptors

趋化因子及其受体的病理生理学和免疫药理学研究

• 批准号: 10044254
• 负责人: MUKAIDA Naofumi
• 金额: $ 5.44万
• 依托单位: Kanazawa University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (A).
• 财政年份: 1998
• 资助国家: 日本
• 起止时间: 1998 至 1999
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10044254/
• 关键词: Interleukin-8 (IL-8); monocyte chemoattractant protein-1 (MCP-1); neutrophil; macrophage; macrophage inflammatory protein (MIP)-1α; angiogenesis; interferon (INF)-γ; renal diseases; NF-κB; AP-1; MCP-1; エオタキシン; ケモカイン; 転移; MIP-2; IL-8; IL-10

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

本研究旨在阐明趋化因子及其受体在各种疾病中的病理生理作用。1）小鼠排卵后阴道上皮细胞周期性地产生巨噬细胞炎性蛋白（MIP）-2，MIP-2是人白细胞介素-8（IL-8）的功能同源物。此外，局部产生的MIP-2参与了排卵后中性粒细胞向阴道的迁移。2）皮下注射野百合碱可引起大鼠慢性肺动脉高压并伴有肺内巨噬细胞浸润。在巨噬细胞浸润开始时产生单核细胞趋化蛋白（MCP）-1。施用抗MCP-1抗体减少巨噬细胞浸润并减轻肺动脉高压。这些结果表明MCP-1通过诱导巨噬细胞浸润参与野百合碱诱导的肺动脉高压的发病机制。 ...更多信息 伊加肾病患者尿IL-8水平升高，而尿MCP-1水平无升高。相反，在容易发展为慢性肾衰竭的慢性型伊加肾病中，尿MCP-1水平显著升高，而尿IL-8水平则没有。此外，我们发现尿MIP-1 α和MCP-1水平分别与慢性新月体肾炎的新月体形成和间质病变相关。因此，各种趋化因子在患病肾脏局部和差异产生，从而有助于建立各种肾脏病变。4）通过IL-8 cDNA转染到胃癌细胞系中增强血管生成和肿瘤形成。此外，我们观察到IL-8 mRNA和蛋白在肿瘤部位坏死区附近的表达。因为接近坏死的区域被认为是缺氧的，我们使人卵巢癌和黑色素瘤细胞系缺氧。缺氧激活两种类型的转录因子AP-1和NF-κ B D2 K和NF-κ B D2 B，从而诱导IL-8的产生。此外，我们获得了人胃癌细胞上存在IL-8受体的明确证据。总的来说，这些结果表明IL-8可能通过诱导血管生成和改变癌细胞的表型参与肿瘤进展。5）我们观察到C5 a激活AP-1和NF-κ B D2 K活化D2 B，从而诱导人单核细胞系产生IL-8。6）我们获得的证据表明，γ-干扰素参与痤疮丙酸杆菌致敏小鼠的肉芽肿形成，通过调节巨噬细胞浸润和几种细胞因子（包括肿瘤坏死因子（TNF）-α、IL-12和IL-18）的产生，诱导肝组织损伤。少

项目成果

Yokoyama, H., Wada, T., Furuichi, K., Segawa, C., Mukaida, N., et al.: "Urinary levels of chemokines (MCAF and IL-8) reflect distinct disease activities and phases of IgA nephropathy"Journal of Leukocyte Biology. 63. 493-499 (1998)

Yokoyama, H.、Wada, T.、Furuichi, K.、Sekawa, C.、Mukaida, N.等人：“趋化因子（MCAF 和 IL-8）的尿液水平反映了 IgA 肾病的不同疾病活动和阶段

Mukaida, N., Harada, A., and Matsushima, K.: "Interleukin-8 and monocyte chemotactic and activating factor (MCAF/MCP-1), chemokines essentially involved in inflammatory and immune reactions (Invited review)"Cytokine and Growth Factor Reviews. 9. 9-23 (199

Mukaida, N.、Harada, A. 和 Matsushima, K.：“白细胞介素 8 和单核细胞趋化和激活因子 (MCAF/MCP-1)，趋化因子主要参与炎症和免疫反应（特邀评论）”细胞因子和生长

Wada, T., Furuichi, K., Segawa, C., Shimizu, M., Sakai, N., Takeda, S. -I., Takasawa, K., Kida, H., Kobayashi, K. -I., Mukaida, N., Ohmoto, Y., Matsushima, K., Yokoyama, H.: "MIP-1α and MCP-1 contribute to crescents and interstitial lesions via the cognat

和田，T.，古市，K.，濑川，C.，清水，M.，酒井，N.，武田，S.-I.，高泽，K.，木田，H.，小林，K.-I。 ，Mukaida，N.，Ohmoto，Y.，Matsushima，K.，Yokoyama，H.：“MIP-1α 和 MCP-1 通过同源基因促进新月体和间质病变

Tsuji, K., Mukaida, N., Harada, A., Kaneko, S., Matsushita, E., et al.: "Alleviation of lipopolysaccharide-induced acute liver injury in Propionibacterium acnes-primed IFN-γ-deficient mice by a concomitant reduction of TNF-α, IL-12 and IL-18 production"Jo

Tsuji, K.、Mukaida, N.、Harada, A.、Kaneko, S.、Matsushita, E. 等人：“通过痤疮丙酸杆菌引发的 IFN-γ 缺陷小鼠减轻脂多糖诱导的急性肝损伤TNF-α、IL-12 和 IL-18 产生同时减少“Jo

Sonoda, Y., Mukaida, N., Wang, J. -b., Shimada-Hiratsuka, M., Naito, M., Kasahara, T., Harada, A., Inoue, M., Matsushima, K.: "Physiologic regulation of postovulatory neutrophil migration into vagina by a C-X-C chemokine(s)."Journal of Immunology. 160. 61

Sonoda, Y.、Mukaida, N.、Wang, J. -b.、Shimada-Hiratsuka, M.、Naito, M.、Kasahara, T.、Harada, A.、Inoue, M.、Matsushima, K.：