Serglycin inhibits the classical and lectin pathways of complement via its glycosaminoglycan chains: implications for multiple myeloma.
Serglycin (SG) is a proteoglycan expressed by hematopoietic cells and is constitutively secreted by multiple myeloma (MM) cells. SG participates in the regulation of various inflammatory events. We found that SG secreted by human MM cell lines inhibits both the classical and lectin pathways of complement, without influencing alternative pathway activity. The inhibitory effect of SG is due to direct interactions with C1q and mannose-binding lectin (MBL). C1q-binding is mediated through the glycosaminoglycan moieties of SG, whereas MBL binds additionally to SG protein core. Interactions between SG and C1q as well as MBL are diminished in the presence of chondroitin sulfate type E. In addition, we localized the SG-binding site to the collagen-like stalk of C1q. Interactions between SG and C1q as well as MBL are ionic in character and only the interaction with MBL was found to be partially dependent on the presence of calcium. We found the serum levels of SG to be elevated in patients with MM compared to healthy controls. Moreover, we found that SG expressed from myeloma plasma cells protects these cells from complement activation induced by treatment with anti-thymocyte immunoglobulins. This might protect myeloma cells during immunotherapy and promote survival of malignant cells.
Department of Chemistry, Laboratory of Biochemistry, University of Patras, Patras, Greece.
Antonis
A
Skliris
Kaisa E
KE
Happonen
Evangelos
E
Terpos
Vassiliki
V
Labropoulou
Magne
M
Børset
Dick
D
Heinegård
Anna M
AM
Blom
Achilleas D
AD
Theocharis
D000368:Aged; D000818:Animals; D000912:Antibodies, Neoplasm / Q000276:immunology; D001665:Binding Sites / Q000276:immunology; D045744:Cell Line, Tumor; D015922:Complement C1q / Q000378:metabolism; D003179:Complement C3b / Q000378:metabolism; D015935:Complement C4b / Q000378:metabolism; D003170:Complement Pathway, Alternative / Q000187:drug effects; D003171:Complement Pathway, Classical / Q000187:drug effects* / Q000276:immunology; D037582:Complement Pathway, Mannose-Binding Lectin / Q000187:drug effects* / Q000276:immunology; D003165:Complement System Proteins / Q000378:metabolism; D005260:Female; D006025:Glycosaminoglycans / Q000378:metabolism* / Q000494:pharmacology; D006461:Hemolysis / Q000187:drug effects / Q000276:immunology; D006801:Humans; D008297:Male; D037601:Mannose-Binding Lectin / Q000378:metabolism; D008875:Middle Aged; D009101:Multiple Myeloma / Q000097:blood / Q000276:immunology*; D011485:Protein Binding / Q000187:drug effects / Q000276:immunology; D011509:Proteoglycans / Q000097:blood / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology*; D011817:Rabbits; D012756:Sheep; D033921:Vesicular Transport Proteins / Q000097:blood / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology*
D000912:Antibodies, Neoplasm; D006025:Glycosaminoglycans; D037601:Mannose-Binding Lectin; D011509:Proteoglycans; D033921:Vesicular Transport Proteins; C075430:serglycin; D015922:Complement C1q; D003179:Complement C3b; D015935:Complement C4b; D003165:Complement System Proteins