Synthesis of α1-Antichymotrypsin and α1-Antitrypsin by Human Trophoblast

Abstract

ABSTRACT. al-Antichymotrypsin (al-ACHY) and al-an-(I). al-AT and aI-ACHY play major roles in the host response titrypsin (al-AT) are closely related glycoprotein protease to trauma and inflammation. The major function of aI-AT, inhibitors, present in plasma and other extracellular fluids, which is present at high levels in human plasma (1 5 3 . 5 mg/ that neutralize proteases released by leukocytes in re-mL), is to inhibit elastases released by leukocytes at sites of sponse to trauma and inflammatory stimuli. Both inhibitors inflammation. al-ACHY, present in plasma at lower levels (0.3-are synthesized primarily by hepatocytes, although lower 0.6 mg/mL), is thought to neutralize ch~motry~sin-like Proteases levels of synthesis by monocytes and breast and intestinal S U C~ aS cathepsin G also released by leukocytes at inflammatory epithelial cells have been demonstrated. Recently, the im-sites. a,-ACHY and (UI-AT belong to the serpin supergene family m u n o~i s t o c~e m i c a~ localization of a l -~~ and aI-~~-~~ in as does CBG, the major glucocorticoid camer in the circulation intrauterine and extrauterine human trophoblastic tissue (2). CBG is cleaved by elastase at a unique site in its C-terminal has been reported.the present study, we have sought to region resulting in decreased glucocorticoid binding (3). Because determine whether human trophoblast is also able to syn-local elastase levels depend to a large degree on local levels of althesize al-AT andMessenger RNA for both AT, delivery of glucocorticoids to inflammatory sites may be inhibitors was found by Northern blotting in chorionic villi regulated by a mechanism involving the interaction of elastase and aI-AT. obtained from first trimester and term placenta. SubstanaI-AT and are synthesized primarily by hepatocytes tial differences in messenger levels for both inhibitors and to a lesser degree by monocytes (4). We have shown that among individual placentas were noted' al-ACHY and al-MCF-7 human breast cancer cells, a cell line of epithelial AT messenger was present in trophoblast in can also synthesize these protease inhibitors and that their synprimary culture. Synthesis of al-AT and al-ACHY protein thesis can be stimulated by steroid hormones, cytokines, and was demonstrated by SDS-PAGE after immuno~reci~ita-growth factors (5). ~l t h o u g h the amount of al-AT and aI-ACHY tion of 135S1-labeled ~I -A T and a]-ACHY from conditioned produced by nonhepatic cells is small in comparison to that media of trophoblast cells in culture metabolically labeled by hepatocytes, local synthesis may be important at with [35S]-methionine. It is of some interest that the M, of sites of inflammation, particularly at locations not directly in the al-AT and ffl-ACHY secreted by trophob1ast contact with the circulation where levels of al-AT and aI-ACHY 50 000 and 49 000, respectively, compared with 54 000 and may only be a fraction of that in plasma (6). Implantation of the 6 8 000 for these proteins in plasma (or secreted by H~P G~ embryo in the uterus elicits an inflam...

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