LARSEN Chris デンマーク王国国立Aarhus大学, 医学部, 助教授
OPPENHEIM Jo 米国国立癌研究所, 研究室主任
西堀 宗樹 金沢大学, がん研究所, 非常勤研究員
AKIYAMA Mariko Cancer Research Institute, Kanazawa University Research Associate, がん研究所, 助手 (60019867)
KASAHARA Tadashi Kyoritu Pharmaceutical College Professor, 薬学部, 教授 (60049096)
JOOST J. Oppenheim 米国, 国立・癌研究所, 研究室主任
CHRISTIAN G. Larsen デンマーク王国, 国立・Aarhus大学・医学部, 助教授
|Budget Amount *help
¥8,500,000 (Direct Cost : ¥8,500,000)
Fiscal Year 1999 : ¥3,900,000 (Direct Cost : ¥3,900,000)
Fiscal Year 1998 : ¥4,600,000 (Direct Cost : ¥4,600,000)
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
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