Am. J. Respir. Crit. Care Med., Vol 157, No. 1, Jan 1998, 246-255.
Alpha 1-antitrypsin and protease complexation is induced by lipopolysaccharide, interleukin-1beta, and tumor necrosis factor-alpha in monocytes [In Process Citation]
DL Knoell, DR Ralston, KR Coulter and MD Wewers
College of Pharmacy, Pulmonary and Critical Care Division, Ohio State University, Columbus 43210, USA.
Local regulation of alpha1-antitrypsin (alpha1-AT) may have importance in
maintenance of the protease-antiprotease balance in the microenvironment of
inflammatory cells. We therefore studied whether lipopolysaccharide (LPS),
interleukin-1beta (IL-1beta), and tumor necrosis factor-alpha (TNFalpha)
affect the pericellular concentration of alpha1-AT in human peripheral
blood mononuclear cells (PBMC). PBMC taken from normal healthy volunteers
were treated with LPS, IL-1beta, and TNFalpha, and the concentration of
human alpha1-AT in conditioned supernatants was measured. When compared
with unstimulated control supernatants (147 +/- 19 ng/ml), LPS (439 +/- 66
ng/ml; p < or = 0.001), IL-1beta (263 +/- 37 ng/ml; p < or = 0.01),
and TNFalpha (316 +/- 59 ng/ml; p < or = 0.05) induced a 2- to 3-fold
increase of alpha1- AT. Up-regulation of alpha1-AT protein correlated with
an increase in alpha1-AT mRNA, suggesting a simultaneous increase in
alpha1-AT synthesis. Despite the increase in alpha1-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 alpha1-AT measured in
supernatants. These findings suggest that local inflammatory conditions
up-regulate alpha1-AT production by monocytes which complex with a protease
derived from the PBMC population.
