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Hepatoma Cells and Human Monocytes DAVID H Proc. Nati. Acad. Sci. USA Vol. 87, pp. 3753-3757, May 1990 Cell Biology Identification of a serpin-enzyme complex receptor on human hepatoma cells and human monocytes DAVID H. PERLMUTTER*t*, GEORGE I. GLOVER§, MEHERYAR RIVETNA§, CHARLES S. SCHASTEEN§, AND ROBERT J. FALLON* Departments of *Pediatncs and tCell Biology and Physiology, Washington University School of Medicine, Saint Louis, MO 63110; and §Department of Biological Sciences, Monsanto Corporation, Chesterfield, MO Communicated by Emil R. Unanue, February 12, 1990 ABSTRACT Formation of the covalently stabilized com- inhibitor, heparin cofactor II (HC II), a2-antiplasmin, protein plex of a1-antitrypsin (a,-AT) with neutrophil elastase, the C inhibitor, plasminogen activator inhibitors I and II, and archetype of serine proteinase inhibitor serpin-enzyme com- protease nexins I and II (reviewed in ref. 4). Although there plexes, is associated with structural rearrangement of the is only 25-30o primary sequence homology among the a,-AT molecule and hydrolysis of a reactive-site peptide bond. members of this family, there is a much greater degree of An =4-kDa carboxyl-terminal cleavage fragment is generated. functional similarity and a similar mechanism ofaction. Each a1-AT-elastase complexes are biologically active, possessing serpin binds its target enzyme at a substrate-like region chemotactic activity and mediating increases in expression of within the carboxyl-terminal portion of the molecule. The the a,-AT gene in human monocytes and macrophages. This enzyme is inactivated as a covalently stabilized enzyme- suggested that structural rearrangement of the a,-AT mole- inhibitor complex is formed. During complex formation there cule, during formation of a complex with elastase, exposes a is also structural rearrangement of the inhibitor and hydrol- domain that is recognized by a specific cell surface receptor or ysis of the reactive-site peptide bond. However, it is not yet receptors. To test this hypothesis, the known three-dimensional known whether hydrolysis of the reactive-site peptide bond structure of al-AT and comparisons of the primary structures goes to completion or whether the carboxyl-terminal frdg- of the serpins were used to select a potentially exteriorly ment is dissociated from the macromolecular complex (re- exposed and highly conserved region in the complexed form of viewed in ref. 3). a,-AT as a candidate ligand (carboxyl-terminal fragment, Several recent studies suggest that a1-AT-elastase com- amino acids 359-374). We show here that synthetic peptides plexes have intrinsic functional activities. These complexes based on the sequence of this region bind specifically and stimulate neutrophil chemotaxis (5) and mediate increases in saturably to human hepatoma cells and human monocytes (Kd expression of the a1-AT gene in human monocytes and = 4.0 x 10-8 M, 4.5 x 105 plasma membrane receptors per macrophages (6, 7). a1-AT-elastase complexes are more cell) and mediate increases in synthesis of a,-AT. Binding of rapidly cleared from the circulation than the corresponding peptide 105Y (Ser-Ile-Pro-Pro-Glu-Val-Lys-Phe-Asn-Lys- native proteins. In fact, in vivo clearance of a1-AT-elastase Pro-Phe-Val-Tyr-Leu-Ile) is blocked by a1-AT-elastase com- complexes is blocked by other serpin-enzyme complexes (8, plexes, antithrombin mI (AT I1)-thrombin complexes, a,- 9), suggesting the presence of a common recognition system. antichymotrypsin (a1-ACT)-cathepsin G complexes, and, to a Taken together, these observations suggest that structural lesser extent, complement component C1 inhibitor-Cls com- rearrangement of the a1-AT molecule, during formation of a plexes, but not by the corresponding native proteins. Binding complex with elastase, exposes a domain that is recognized of peptide lO5Y is also blocked by peptides with sequence by a specific cell surface receptor, or receptors. In the corresponding to carboxyl-terminal fragments of the serpins following study we used synthetic peptides based on the AT Im and a,-ACT, but not by peptides having the sequence sequence of the carboxyl-terminal fragment of a1-AT as of the extreme amino terminus of a,-AT. The results also show candidate mediators for regulation of a1-AT synthesis and as that peptide 105Y inhibits binding of 125I-labeled a1-AT- candidate ligands for cell surface binding. This region of the elastase complexes. Thus, these studies demonstrate an abun- a1-AT molecule was selected because it had been previously dant, relatively high-afflinity cell surface receptor which rec- implicated in the chemotactic activity of a1-AT-elastase ognizes serpin-enzyme complexes (SEC receptor). This recep- complexes (5) and because crystal structure analysis (10) tor is capable ofmodulating the production ofat least one ofthe predicted that a domain within this region was exteriorly serpins, a,-AT. Since the ligand specifcity is similar to that exposed after formation of a complex. previously described for in vivo clearance of serpin-enzyme complexes, the SEC receptor may also be involved in the EXPERIMENTAL PROCEDURES clearance of certain serpin-enzyme complexes. Materials. Peptides were synthesized by the solid-phase method (11, 12), purified, and subjected to amino acid a1-Antitrypsin (a,-AT) is a 55-kDa serum glycoprotein that composition and sequence analysis. Peptides were dissolved inactivates neutrophil elastase. Since neutrophil elastase is in water and then added to cell culture fluid. Preparation of capable of degrading most of the constituents of connective purified human plasma a1-AT, leukocyte elastase, and leu- tissue matrices, its inhibitor a,-AT is thought to play a critical kocyte cathepsin G has been previously described (6). Puri- role in connective tissue turnover in homeostasis and tissue fied human plasma AT III and a,-ACT were purchased from injury/inflammation (reviewed in refs. 1-3). Athens Research and Technology (Athens, GA). Purified a,-AT is the archetype of the serine proteinase inhibitor human thrombin was purchased from Boehringer-Mann- (serpin) family, which includes antithrombin III (AT III), a1-antichymotrypsin (a,-ACT), complement component Ci Abbreviations: a1-AT, a1-antitrypsin; AT III, antithrombin III; a,- ACT, a1-antichymotrypsin; serpin, serine proteinase inhibitor; SEC, serpin-enzyme complex. The publication costs of this article were defrayed in part by page charge tTo whom reprint requests should be addressed at: Department of payment. This article must therefore be hereby marked "advertisement" Pediatrics, Washington University School of Medicine, 400 S. in accordance with 18 U.S.C. §1734 solely to indicate this fact. Kingshighway Boulevard, Saint Louis, MO 63110. 3753 Downloaded by guest on September 24, 2021 3754 Cell Biology: Perlmutter et al. Proc. Natl. Acad, Sci. USA 87 (1990) heim. Human complement component Cls was a gift from a DavidBing (Boston, MA) and Cl inhibitor was from Alvin E. I.552 360 370 3830 Davis (Boston, MA). Recombinant yeast-derived [Val358a1- FLEAIPMSIPPEVKFNKPFVFLMIEQNTK AT was kindly provided byI. Bathurst and P. Barr (Em- eryville, CA). 105 I- -II Cell Culture. Confluent monolayers of human blood mono- cytes from normal individuals were established by a previ- 105Y I- -Y- IJI ously described technique (13). HepG2 cells were maintained 109 I II in culture as previously described (13). 113 Metabolic Labeling. Confluent monolayers were rinsed and |IVIcII| incubated at 370C in the presence of medium containing [35S]methionine at250,uCi/ml (1 Ci = 37 GBq). To determine b C the net synthesis ofa1-AT and a control protein, factor B, cells were subjected to a short pulse (20 min) and radiolabeled a1-AT or factor B was assayed in the cell lysates. Solubili- zation ofcells, clarification ofcell lysates after labeling, assay of total protein synthesis, immunoprecipitation, and SDS- PAGE have been described (13-15). 400 mpqwqmq Deterinination of Cell Surface Receptor Binding. Peptide 46 lO5Y was labeled with 125I by using chloramine T and was Vo i At a - :3;! AsIC* purified by gel filtration onBio-Gel P2(Bio-Rad). The specific CaI- - At "wd :I '. I- (! . NterM!L,'-;aO-;o-, F radioactivity of various preparations was 1500-3000 cpm/ng 'Af of peptide. Recombinant [Val358]a1-AT was labeled with1251 (ngmi by using lodobeads (Pierce) and purified by gel filtration through Sephadex G-10 (Pharmacia). The specific radioactiv- FIG. 1. Effect of synthetic peptides on synthesis of a,-AT in ity was 1000-5000 cpm/ng of protein. For binding studies, human monocytes. (a) Amino acid sequences of a,-AT and several cells were washed with Dulbecco's phosphate-buffered saline synthetic peptides. (b) Monolayers of peripheral blood monocytes and incubated at 40C for 2 hr with 125I-labeled peptide105Y were incubated for 10 hr at 370C in control serum-free medium, (1251-peptide105Y) or [Val358]a,-AT diluted in Dulbecco's medium supplemented with human neutrophil elastase (50 ng/ml), or modified Eagle's medium containing 10 mM Hepes and cy- medium supplemented with peptide 113 in the specified concentra- tions. (c) Monocytes were incubated for 10 hr at 370C in control tochrome c at 0.1 mg/ml. The cells were then rinsed in serum-free medium, medium supplemented with human neutrophil phosphate-buffered saline and homogenized in 1 M Na6H, elastase (50 ng/ml), Escherichia coli lipopolysaccharide (LPS; 100 and cell-associated radioactivity was determined. Specific ng/ml), LPS and polymyxin B (15ug/ml), or synthetic peptides in binding of iodinated ligand was defined as the difference the specified concentrations together with polymyxin B. Cells were between total and nonspecific binding. Nonspecific binding then subjected to metabolic labeling, and radiolabeled cell lysates was determined by the addition of a 200-fold excess of unla- were subjected to immunoprecipitation with anti-human a1-AT fol- beled ligand. Scatchard plot analysis of equilibrium binding lowed by SDS/PAGE/fluorography. The sequence ofpeptide Nterm data was performed as previously described (16, 17). is EDPQGDAAQ. Molecular weight markers are indicated at the right margin.
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