␣ 1 -Antichymotrypsin (ACT) is an acute phase protein expressed in the brain which specifically colocalizes with amyloid- during Alzheimer's disease. We analyzed ACT synthesis in cultured human cortical astrocytes in response to various cytokines and growth factors. Oncostatin M (OSM) and interleukin (IL)-1 were potent stimulators of ACT mRNA expression, whereas tumor necrosis factor-␣ had modest activity, and IL-6 and leukemia inhibitory factor (LIF) were ineffective. The finding that OSM, but not LIF or IL-6, stimulated ACT expression suggests that human astrocytes express a "specific" OSM receptor, but not IL-6 or LIF receptors. However, cotreatment of human astrocytes with soluble IL-6 receptor (sIL-6R)⅐IL-6 complex did result in potent stimulation of ACT expression. When the human ACT gene was cloned, two elements binding STAT1 and STAT3 (signal transducer and activator of transcription) in response to OSM or IL-6⅐sIL-6R complexes could be identified and characterized. Taken together, these findings indicate that OSM or IL-6⅐sIL-6 complexes may regulate ACT expression in human astrocytes and thus directly or indirectly contribute to the pathogenesis of Alzheimer's disease.1 is one of the major positive human acute phase proteins produced by the liver and secreted into blood plasma (1, 2). The expression of this proteinase inhibitor in hepatic cells is enhanced by interleukin (IL)-6 and glucocorticoids and to a lesser extent by IL-1 (3, 4). Although ACT is also found in the brain, the plasma-derived inhibitor is separated from this origin by a tight blood-brain barrier consisting of endothelial cells. For this reason it is believed that astrocytes are the likely source of ACT produced within the central nervous system (5). Significantly, ACT has been identified as one of the amyloid-associated proteins found in the brains of patients with Alzheimer's disease (6, 7). The pathological feature of this disease is cerebral degeneration with neuronal cell death and deposition of abnormal proteins in the form of amyloid plaques and neurofibrillary tangles. Because the expression of ACT is enhanced dramatically in affected brain regions in Alzheimer's disease, a state of cerebral "acute phase" in response to neuronal degradation has been proposed. IL-1 and IL-6, which are produced by cells of CNS, were suggested to induce ACT expression in astrocytes (8). Indeed, the induction of ACT expression by IL-1 has been shown in human astrocyte cultures (9); however, regulation by IL-6 has not been confirmed.To understand the control of ACT expression in the brain we used human astrocyte cultures and analyzed the pattern of its synthesis after stimulation with a variety of factors including IL-1 and cytokines of the IL-6 family. We have also cloned the 5Ј-flanking region of the ACT gene and performed analysis of its transcriptional activity. Our results suggest that at least one cytokine, oncostatin M (OSM), may play an important role in up-regulating ACT expression in astrocytes, whereas IL-6 requires the presence of solu...