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

Abstract

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.

Effect of Pseudomonas Elastase on Human Mononuclear Phagocyte α1-Antitrypsin Expression

“…Second, there is a correlation between the time frame within which pseudomonas elastase affects al-AT synthesis and the time frame for uptake and removal of pseudomonas elastase from its putative substrate. Third, a pretranslational mechanism is re-sponsible for the effect of pseudomonas elastase on al-AT gene expression as well as for signals transduced by the SEC receptor (1 [8][9][10][11][12][13][14][15][16][17][18][19][20]. Finally, the regulatory effect of pseudomonas elastase on al-AT synthesis is specifically blocked by antibody to the domain of al-AT that is recognized by the SEC receptor.…”

“…The mechanism by which neutrophil elastase-al-AT and proteolytic inactivated al-AT regulate mononuclear phagocyte a,-AT gene expression has been the subject of detailed investigation (1 [8][9][10][11][12][13][14][15][16][17][18][19][20]. We have recently shown that a region within the carboxy terminal fragment of al-AT is recognized by an abundant highafinity receptor, SEC receptor, on the plasma membrane of human hepatoma-derived hepatocytes and human mononuclear phagocytes (20).…”

“…We now know that synthesis of a,-AT in hepatocytes is regulated by the acute phase mediator IL-6 (16). Synthesis of al-AT in mononuclear phagocytes is regulated by IL-6 (16), bacterial LPS (17), and a novel feedback mechanism involving the neutrophil elastase-al-AT complex as mediator (18)(19)(20). In the last case, a domain in the carboxy-terminal fragment of al-AT is newly exposed during the formation of the elastase-al-AT complex.…”

“…RNA was subjected to agaroseformaldehyde gel electrophoresis and transferred to nitrocellulose filters (35). Filters were then hybridized with 32P-labeled cDNA specific for human al-AT (17).…”

Cell-specific expression of alpha 1-antitrypsin in human intestinal epithelium.

“…These studies did not, however, exclude the possibility that such a,-AT mRNA was derived from macrophages resident in the lamina propria or submucosal layers of the intestine. Synthesis of a,-AT has been demonstrated in a human intestinal adenocarcinoma cell line Caco2 (8). There is a marked increase in synthesis of a,-AT in Caco2 cells as they spontaneously differentiate from cryptlike to villouslike enterocytes.…”