INTERLEUKIN-1-BETA AND TUMOR-NECROSIS-FACTOR-ALPHA INDUCE EXPRESSION OF ALPHA(1)-ANTICHYMOTRYPSIN IN HUMAN ASTROCYTOMA-CELLS BY ACTIVATION OF NUCLEAR FACTOR-KAPPA-B

The protease inhibitor alpha(1)-antichymotrypsin (ACT) has been sugges ted to be involved in the etiology of Alzheimer's disease (AD). Increa sed levels of ACT have been found in serum and brains of AD patients, and ACT has been proposed to regulate beta-amyloid fibril formation in vitro. To gain insight into the regulation of ACT in the brain, we in vestigated the signal transduction pathways involved in ACT gene expre ssion and protein synthesis in the human astrocytoma cell line U373. T his cell line has previously been shown to respond with strong ACT syn thesis on stimulation with interleukin-1 beta (IL-1 beta) or tumor nec rosis factor-alpha (TNF alpha). Here, we describe that both IL-1 beta and TNF alpha activate the transcription factor nuclear factor-kappa B (NF-kappa B) via production of reac tive oxygen intermediates resulti ng in ACT expression. In addition, we show that neither protein kinase C nor protein kinase A is involved in IL-1 beta- or TNF alpha-induced ACT expression. These results suggest that activation of NF-kappa B m ay be one possible cause of increased ACT levels in AD and provide a b asis for the development of drugs used for the modulation of inflammat ory processes occurring in AD.