Alpha 1-antitrypsin and protease complexation is induced by lipopolysaccharide, interleukin-1β, and tumor necrosis factor-α in monocytes

Local regulation of alpha 1-antitrypsin ( alpha 1-AT) may have importance in maintenance of the protease-antiprotease balance in the microenvironment of inflammatory cells. We therefore studied whether lipopolysaccharide (LPS), interleukin-1 beta (IL-1 beta ), and tumor necrosis factor- alpha (TNF alpha ) affect the pericellular concentration of alpha 1-AT in human peripheral blood mononuclear cells (PBMC). PBMC taken from normal healthy volunteers were treated with LPS, IL-1 beta , and TNF alpha , and the concentration of human alpha 1-AT in conditioned supernatants was measured. When compared with unstimulated control supernatants (147 plus or minus 19 ng/ml), LPS (439 plus or minus 66 ng/ml; p less than or equal to 0.001), IL-1 beta (263 plus or minus 37 ng/ml; p less than or equal to 0.01), and TNF alpha (316 plus or minus 59 ng/ml; p less than or equal to 0.05) induced a 2- to 3-fold increase of alpha 1-AT. Up-regulation of alpha 1-AT protein correlated with an increase in alpha 1-AT mRNA, suggesting a simultaneous increase in alpha 1-AT synthesis. Despite the increase in alpha 1-AT concentration, functional antiprotease activity could not be detected. Furthermore, protease activity was present in all samples, with the amount of activity being inversely related to the amount of alpha 1-AT measured in supernatants. These findings suggest that local inflammatory conditions up-regulate alpha 1-AT production by monocytes which complex with a protease derived from the PBMC population.