Novel stabilin-1 interacting chitinase-like protein (SI-CLP) is up-regulated in alternatively activated macrophages and secreted via lysosomal pathway.
Mammalian Glyco_18-domain-containing proteins include catalytically active chitinases and chitinase-like proteins with cytokine activity involved in host defense and Th2-type inflammatory reactions. Here, we describe a novel human Glyco_18-domain-containing protein, SI-CLP, as an interacting partner of the endocytic/sorting receptor stabilin-1. Similarly to the chitinase-like cytokines YKL-39, YKL-40, and YM1/2, SI-CLP lacks a chitin-binding domain and catalytic amino acids. Using a novel mAb 1C11, we demonstrated that SI-CLP is sorted into late endosomes and secretory lysosomes in human alternatively activated macrophages. The direct interaction of SI-CLP with stabilin-1, their colocalization in the trans-Golgi network, and the reduced sorting of SI-CLP into lysosomes in macrophages treated with stabilin-1 siRNA suggest that stabilin-1 is involved in intracellular sorting of SI-CLP. Expression of SI-CLP in macrophages was strongly up-regulated by the Th2 cytokine IL-4 and by dexamethasone. This effect was suppressed by IFNgamma but not affected by IL-10. In contrast, expression of YKL-40 was induced by IFNgamma and suppressed by dexamethasone. Macrophages treated with IL-4 secreted SI-CLP, while costimulation with dexamethasone blocked secretion and resulted in intracellular accumulation of SI-CLP. The 1C11 mAb detected SI-CLP in human bronchoalveolar lavage and peripheral-blood leukocytes (PBLs), and can be used to analyze the role of SI-CLP in human disorders.
Kzhyshkowska
Julia
J
Department of Dermatology, Venerology and Allergology, University Medical Centre Mannheim, Ruprecht-Karls University of Heidelberg, Theodor-Kutzer Ufer 1-3, 68167 Mannheim, Germany. julia.kzhyshkowska@haut.ma.uni-heidelberg.de
Mamidi
Srinivas
S
Gratchev
Alexei
A
Kremmer
Elisabeth
E
Schmuttermaier
Christina
C
Krusell
Liis
L
Haus
Georg
G
Utikal
Jochen
J
Schledzewski
Kai
K
Scholtze
Joachim
J
Goerdt
Sergij
S
D000893:Anti-Inflammatory Agents / Q000276:immunology / Q000494:pharmacology; D001992:Bronchoalveolar Lavage Fluid; D002352:Carrier Proteins / Q000235:genetics / Q000276:immunology*; D015816:Cell Adhesion Molecules, Neuronal / Q000096:biosynthesis / Q000276:immunology*; D002478:Cells, Cultured; D002688:Chitinases / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D016207:Cytokines / Q000276:immunology / Q000494:pharmacology; D003907:Dexamethasone / Q000276:immunology / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D006056:Golgi Apparatus / Q000201:enzymology / Q000276:immunology; D006801:Humans; D007249:Inflammation / Q000201:enzymology / Q000276:immunology; D008247:Lysosomes / Q000276:immunology*; D008262:Macrophage Activation / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D016676:Macrophages, Alveolar / Q000166:cytology / Q000201:enzymology / Q000276:immunology*; D017434:Protein Structure, Tertiary / Q000235:genetics; D021381:Protein Transport / Q000235:genetics / Q000276:immunology; D016201:Receptors, Lymphocyte Homing / Q000096:biosynthesis / Q000276:immunology*; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics / Q000276:immunology
D000893:Anti-Inflammatory Agents; C510246:CHID1 protein, human; D002352:Carrier Proteins; D015816:Cell Adhesion Molecules, Neuronal; D016207:Cytokines; D016201:Receptors, Lymphocyte Homing; C449926:STAB1 protein, human; D003907:Dexamethasone; D002688:Chitinases