The cytokine IFN β2/IL-6 has recently been shown to regulate the expression of genes encoding hepatic acute phase plasma proteins. IFN β2/IL-6 has also been shown to be identical to MGI-2, a protein that induces differentiation of bone marrow precursor cells toward mature granulocytes and monocytes. Accordingly, we have examined the effect of IFN β2/IL-6 on expression of the IL-1- and tumor necrosis factor-unresponsive acute phase protein α1-antitrypsin (α1 AT) in human hepatoma-derived hepatocytes and in human mononuclear phagocytes. Purified human fibroblast and recombinant IFN β2/IL-6 each mediate a specific increase in steady-state levels of α1 AT mRNA and a corresponding increase in net synthesis of α1 AT in primary cultures of human peripheral blood monocytes as well as in HepG2 and Hep3B cells. Thus, the effect of IFN β2/IL-6 on α1 AT gene expression in these cells is primarily due to an increase in accumulation of α1 AT mRNA and can be distinguished from the direct, predominantly translational effect of bacterial lipopolysaccharide on expression of this gene in monocytes and macrophages. The results indicate that IFN β2/IL-6 regulates acute phase gene expression, specifically α1 AT gene expression, in extrahepatic as well as hepatic cell types.