Mononuclear phagocytes are a bone-marrow-derived subgroup of white blood cells which circulate as monocytes and, after differentiation into macrophages, become resident in many tissues. By synthesizing the important proteinase inhibitors a,-macroglobulin and al-proteinase inhibitor mononuclear phagocytes contribute to the control of proteolysis both in blood and tissues. Applying a culture system which enables human blood monocytes to differentiate into macrophages in vitro, synthesis of a,-macroglobulin and al-proteinase inhibitor was studied. The normal course of monocyte -macrophage maturation is accompanied by a strong increase of specific a,-macroglobulin synthesis and a concomitant slight decrease of al-proteinase inhibitor. a,-Macroglobulin can be designated as a marker protein of the monocyte/macrophage differentiation. Endotoxin (Salmonella ryphi) in a concentration as low as 100 ng/ml strongly represses a,-macroglobulin synthesis both in monocytes and macrophages. Furthermore, endotoxin completely abolishes the induction of a,-macroglobulin synthesis during the course of normal monocyte in vitro cultivation, indicating that endotoxin is a strong inhibitor of the monocyte -macrophage maturation. In contrast to a,-macroglobulin, al-proteinase inhibitor synthesis is strongly stimulated by endotoxin in monocytes as well as in macrophages.The cells of the mononuclear phagocyte system derive from stem cells in the bone marrow, linking monoblasts, promonocytes, monocytes and the heterogeneous tissue macrophages (for review see [l -31). Cells of this lineage develop over several days in the marrow and circulate as monocytes in the peripheral blood for a few further days before migrating into different tissues, where they remain resident for up to several months as macrophages. Macrophages are present in the liver (as Kupffer cells), lung (as alveolar macrophages), bone (as osteoclasts) and several other tissues. The development of the blood monocytes into macrophages is accompanied by marked morphological and biochemical changes and is designated as terminal maturation. Differentiation of monocytes into macrophages can be studied in vitro by cultivation of purified populations of human peripheral blood monocytes within hydrophobic Teflon foils in the presence of human serum [4]. In vitro maturation closely resembles differentiation in vivo [5].Secretory products of mononuclear phagocytes are involved in several macrophage functions, such as immunoregulation and the killing of bacteria (for review see [3,61). Several proteinase inhibitors were found to belong to the proteins secreted by mononuclear phagocytes including azCorrespondence to J. Bauer, Medizinische Universitatsklinik, Hugstetter StraSe 55, D-7800 Freiburg, Federal Republic of Germany This work is dedicated to Prof. Dr Georg Wilhelm Lohr on the occasion of his 65th birthday.Abbreviations. E~M , a2-macroglobulin, q P I , ccl-proteinase inhibitor; RPMI, Roswell Park Memorial Institute 1640 medium. macroglobulin (azM) [7] and a]-proteinase inhibitor (a...

The biosynthesis and secretion of M-type and Z-type «i-antitrypsin was studied in human monocytes. In monocytes of PiMM individuals a\-antitrypsin represented 0.08% of the newly synthesized proteins and 0.44% of the secreted proteins. Two molecular forms of a r antitrypsin could be identified: a 51-kDa intracellular form, susceptible to endoglucosaminidase H, thus representing the highmannose type precursor form and a 56-kDa form resistant to endoglucosaminidase H which was secreted into the medium. Inhibition of de novo glycosylation by tunicamycin impaired the secretion of M-type OL\-antitrypsin by about 75% whereas inhibition of oligosaccharide processing by the mannosidase II inhibitor swainsonine did not alter the secretion of Mtype c^-antitrypsin. «i-Antitrypsin secreted by human monocytes was functionally active as measured by complex formation with porcine pancreatic elastase. Even unglycosylated a r antitrypsin secreted by human monocytes treated with tunicamycin formed a complex with elastase. In monocytes of PiZZ individuals the secretion of a r antitrypsin was decreased. 72% of newly synthesized M-type «i-antitrypsin, but only 35% of newly synthesized Z-type a r antitrypsin were secreted during a labeling period of 3 h with [ 35 S]methionine.The 51-kDa form of Z-type «i-antitrypsin accumulated intracellularly, whereas the 56-kDa form was secreted. Inhibition of oligosaccharide processing by swainsonine did not alter the decreased secretion of Z-type a r antitrypsin, whereas inhibition of de novo glycosylation by tunicamycin blocked the secretion of Z-type «i-antitrypsin completely. Biosynthese und Sekretion von M-und Z-Typ-a r Antitrypsin in menschlichen Monozyten. Einflu von Inhibitoren der Glycosylierung und des Oligosaccharid-"Processings" auf Sekretion und FunktionZusammenfassung: Die Biosynthese von M-und ZTyp-a r Antitrypsin wurde in menschlichen Monozyten untersucht. In Monozyten von PiMM-Individuen stellte «i-Antitrypsin 0.08% der neu synthestisierten und 0.44% der sezernierten Proteine dar. Es konnten 2 molekulare Formen von a r Antitrypsin identifiziert werden: eine 51 kDa intrazellul re Form, die Endoglucosaminidase-H-spaltbar war und somit die Mannose-reiche Vorl uferform darstellte, und eine 56-kDa-Form, die nicht durch Endoglucosaminidase H gespalten werden konnte und die ins Medium sezerniert wurde. Hemmung der De-novo-Glycosylierung durch Tunicamycin hemmte die Sekretion von M-Typ-«i-Antitrypsin um etwa 75%, wohingegen eine Hemmung des Oligosaccharid-"Processings" durch den Mannosidase-II-Inhibitor Swainsonin die Sekretion von M-Typ-cxi-Antitrypsin nicht ver nderte. «i-Antitrypsin, das von menschlichen Monozyten sezerniert