| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
* Department of Dermatology, Venerology and Allergology, University Medical Centre Mannheim, Ruprecht-Karls University of Heidelberg, Germany;
Hope Heart Program, Benaroya Research Institute at Virginia Mason, Seattle, WA 98101; and
Center for Molecular Medicine, Institute for Cell Biology, Histology and Embryology, Medical University of Graz, Austria
Alternatively activated (M2) macrophages regulate immune responses and tissue remodelling. In many tissues including placenta, M2 express stabilin-1, a multidomain protein that exerts a dual role as a scavenger receptor for acetylated low density lipoprotein (acLDL) and SPARC (secreted protein acidic and rich in cysteine) and as an intracellular cargo carrier for SI-CLP. Using yeast two-hybrid screening, we identified the developmental hormone placental lactogen (PL) as a novel ligand of stabilin-1. In Chinese hamster ovary-stabilin-1 cells and M2, FACS and confocal microscopy demonstrated that stabilin-1 mediates internalization and endosomal sorting of PL. In M2 macrophages, PL was partially degraded in lysosomes; part of PL escaped degradation and was delivered to novel PL+ storage vesicles lacking endosomal/lysosomal markers. During formation, PL+ vesicles underwent transient interaction with the trans-Golgi network (TGN). Upon placement of PL-loaded M2 into PL-free medium, PL was secreted into the supernatant. Leupeptin, an inhibitor of lysosomal hydrolases, reduced PL degradation, enhanced sorting of PL into the TGN/storage vesicle pathway and increased PL secretion. Thus, processing of PL in M2 macrophages occurs either by the classical lysosomal pathway or by a novel TGN-associated trans-secretory pathway. Macrophages isolated from human placental villi efficiently endocytosed PL-FITC and transported it to the storage vesicles. Our data show that extracellular PL levels are determined by uptake, degradation, storage, and release in M2. During pregnancy PL concentration reaches 10 µg/ml in maternal circulation and stays below 0.5 µg/ml in fetal circulation. We propose that stabilin-1-positive macrophages determine the difference in PL levels between maternal and fetal circulation.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by the Margarete von Wrangell Habilitationprogramm (to J.K.), by Grant SFB405 from the Deutsche Forschungsgemeinschaft, by Project B12 (to J.K. and S.G.), by an Ecosystem Management Decision Support travel grant (to J.K.), and by FP6-512040 of the European Commission, Network of Excellence "The Control of Embryo Implantation (EMBIC)" (to P.S.).
2 J.K. and A.G. contributed equally to this work.
3 Address correspondence and reprint requests Dr. Julia Kzhyshkowska, Department of Dermatology, Venerology and Allergology, University Medical Centre Mannheim, University of Heidelberg, Theodor-Kutzer Ufer 1-3, 68167 Mannheim, Germany. E-mail address: julia.kzhyshkowska{at}haut.ma.uni-heidelberg.de
4 Abbreviations used in this paper: acLDL, acetylated low density lipoprotein; CHO, Chinese hamster ovary; PL, placental lactogen; hPL, human PL; TGN, trans-Golgi network; SI-CLP, stabilin-1 chitinase-like protein.
This article has been cited by other articles:
|
|
 |
|
  L. J Oliveira and P J Hansen Deviations in populations of peripheral blood mononuclear cells and endometrial macrophages in the cow during pregnancy Reproduction, October 1, 2008; 136(4): 481 - 490. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
