Lipopolysaccharide modulates the expression of alpha 1 proteinase inhibitor and other serine proteinase inhibitors in human monocytes and macrophages.

摘要

alpha 1 Proteinase inhibitor (PI) is the principle inhibitor of neutrophil elastase, an enzyme that degrades many components of the extracellular matrix. Expression and regulation of alpha 1 PI, therefore, affects the delicate balance of elastase and antielastase, which is critical to turnover of connective tissue during homeostasis, tissue injury, and repair. In this study we show that expression of alpha 1 PI in human monocytes and macrophages is regulated during activation by LPS. LPS mediates a concentration- and time-dependent increase in the rate of synthesis of alpha 1 PI in mononuclear phagocytes. There is a 4.5-8.7-fold increase in functionally active inhibitor delivered to the cell culture fluid of monocytes. The effect of LPS is specific in that it is neutralized by an mAb to the lipid A moiety. The increase in expression of alpha 1 PI mediated by LPS occurs in the context of other specific changes in the expression of serine proteinase inhibitor genes in mononuclear phagocytes. There is an increase in the rate of synthesis of C1 inhibitor and a decrease in synthesis of alpha 2 macroglobulin. Regulation of alpha 1 PI by LPS is distinctive in that it is largely determined by a change in the efficiency of translation of alpha 1 PI mRNA. LPS has no effect on the rate of posttranslational processing and/or secretion of alpha 1 PI and, therein, causes greater intracellular accumulation of alpha 1 PI in mononuclear phagocytes from individuals with homozygous PiZZ alpha 1 PI deficiency.