White matter astrocytes produce hepatocyte growth factor activator inhibitor in human brain tissues.

Hepatocyte growth factor (HGF) is a potent mitogen for mature hepatocytes and also has multifunctional effects on some other cells in various organs. A HGF activator (HGFA) has been identified as a key enzyme that regulates the activity of HGF in vivo. Our previous studies have shown that brain astrocytes produce both proteins. Recently, HGFA inhibitor-1 (HAI-1), a novel Kunitz-type serine protease inhibitor, has been isolated. We examined HAI-1 immunolabeling in the brains of neurologically normal persons and patients with Alzheimer's disease (AD) and cerebral infarction. Furthermore, we identified the expression of the mRNA for HAI-1 by in situ hybridization histochemistry. The HAI-1 antibody stained astrocytes in the white matter of all brain tissues and was present in plasma. In AD, the intensity of HAI-1 immunolabeling was less than in the other cases. Expression of the mRNA for HAI-1 was also seen in astrocytes. The intensity of the signal for HAI-1 mRNA was similar in AD and normal control brains. These results suggest that, in human brain, secreted pro-HGF from astrocytes may be activated by HGFA and inhibited by HAI-1 on or near the astrocytic cell surface and that rapid HAI-1 consumption may occur in the white matter in AD.