α 1 -antitrypsin (AAT) is the archetypal member of the serine proteinase inhibitor (SERPIN) gene family. AAT is an acute-phase reactant and the plasma concentration increases three- to four-fold during the inflammatory response. In hepatocytes this increase is mediated primarily by the cytokine interleukin-6 (IL-6) via the transcription factor NF-IL6. The AAT gene contains at least two enhancer elements, one at the 5 end of the gene and the other at the 3 end. Functional studies performed in mammalian hepatoma cells (Hep G2) using constructs containing these AAT enhancer regions linked to a reporter gene have demonstrated that the 5 enhancer is dominant under basal conditions and that, following stimulation with IL-6, both enhancers are essential and the 3 enhancer plays a major role. We have identified a mutation associated with lung disease which occurs in the 3 AAT enhancer; the mutation occurs at a binding site for the ubiquitous transcription factor Oct-1. The functional significance of this mutation is a deficient IL-6 response. Using the AAT gene as a model, we describe the interactions which occur between transcription factors within the 3 enhancer and also those which take place between the 5 and 3 enhancers. These studies shed light on the molecular mechanism of the acute-phase response which could possibly be extended to other members of the SERPIN gene family.