有村 章 チューレン大学, 米日生物医学研究所, 教授
TAKE Sachiko Kyushu University, Dept.of Physiology, Assistant Professor, 大学院・医学系研究科, 助手 (80253425)
TAKAKI Atsushi Kyushu University, Dept.of Physiology, Assistant Professor, 大学院・医学系研究科, 助手 (30243934)
KATAFUCHI Toshihiko Kyushu University, Dept.of Physiology, Associate Professor, 大学院・医学系研究科, 講師 (80177401)
AOU Shuji Kyushu University, Dept.of Physiology, Associate Professor, 大学院・医学系研究科, 助教授 (40150908)
|Budget Amount *help
¥3,500,000 (Direct Cost : ¥3,500,000)
Fiscal Year 1999 : ¥1,700,000 (Direct Cost : ¥1,700,000)
Fiscal Year 1998 : ¥1,800,000 (Direct Cost : ¥1,800,000)
In this project, in order to clarify the brain-gut-liver-immune-axis in terms of the neuroimmunomodulation under no-inflammatory stress, we, especially, focused on (1) the regulation of the membrane barrier in the gut, (2) the pathway from the gut associated organs to the central nervous system, (3) the brain mechanisms triggered by the peripheral inputs, mainly using in vivo rat model. Main results are summarized as follows.
1) Mild non-inflammatory stresses such as immobilization, electrical foot shock, cage change stress, and heat exposure, induced plasma IL-6 increase.
2) Non-inflammatory stress-induced plasma IL-6 increase appeared to be initiated by the gut-derived LPS.The evidence for this hypothesis were as follows.
i) The LPS levels in the portal and systemic circulation were elevated during and after stresses.
ii) The tissue LPS contents in the mesentery, mesenteric lymph nodes, liver, and spleen were increased during and after immobilization stress and electrical foot shock s
iii) The non-inflammatory stress-induced plasma IL-6 elevation was attenuated by in vivo neutralization of bioactive LPS in circulation.
iv) FITC-labeled LPS, which was injected into the lumen of the ileum through the cannulation implanted, was detected in the portal vein, and the total amount of the FITC-LPS translocated was increased by immobilization stress.
v) About 80% of FITC-LPS positive cells in the liver was also observed IL-6 like immunoreactivity.
vi) Tissue contents of the IL-6 mRNA in the liver was increased by immobilization stress, not in the spleen and the brain.
vii) The IL-6 mRNA expression by in situ immunohistochemistry was dramatically increased in the liver
3) Gelatin-binding-protein 28 (GBP28), which was released from the adipose tissue, could attenuated the LPS bioactivity in vitro, and expression of GBP28 was observed in the matrix of the connective tissue not only in the liver but other tissues. The data suggests that GBP28 functions as a scavenger for the gut derived LPS.
4) The circulating LPS induced the IL-6 expression in the pituitary grand. Since the IL-6 receptor was detected in the LH and/or FSH cells, gut-derived LPS may modify the gonadotropic function.
5) Gut derived LPS and/or bioactive substances induced by LPS reached to the circumventricular organs, which is connected with the hypothalamus in the brain. Less