Interactions of the Extracellular Matrix Proteoglycans Decorin and Biglycan with C1q and Collectins

Groeneveld, Tom W.L.; Oroszlán, Melinda; Owens, Rick T.; Faber-Krol, Maria C.; Bakker, Astrid C.; Arlaud, Gérard J.; McQuillan, David J.; Kishore, Uday; Daha, Mohamed R.; Roos, Anja

doi:10.4049/jimmunol.175.7.4715

Cited by 114 publications

(123 citation statements)

References 31 publications

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“…We found that SG bound to the immobilized collagen-like stalk domain of C1q in a similar manner as biglycan (BGN) used as a positive control [23]. As reported previously [20], the negative control fibromodulin (FM) did not bind C1q stalks (Fig.…”

Section: Sg Binds To C1q Stalkssupporting

confidence: 82%

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Serglycin inhibits the classical and lectin pathways of complement via its glycosaminoglycan chains: Implications for multiple myeloma

et al. 2010

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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 mannosebinding 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.Keywords: Complement . Multiple myeloma . Serglycin Introduction Serglycin (SG) is a proteoglycan with a 17 kDa protein moiety containing a characteristic domain rich in serine/glycine repeats, which serves as the attachment site for glycosaminoglycan (GAG) chains [1]. SG is mainly expressed by cells of hematopoietic origin and is a key intracellular proteoglycan [2,3]. SG can carry eight GAG chains, which depending on cell-type, can be either chondroitin sulfate (CS), dermatan sulfate (DS), heparan sulfate (HS), and heparin [3,4]. SG is constitutively secreted from monocytes [5] and macrophages [6] into the extracellular matrix and the secretion increases upon activation of these cells. The Eur. J. Immunol. 2011. 41: 437-449 DOI 10.1002 Innate immunity 437 biological function of SG is not fully elucidated, but the results obtained from studies with SG-knockout mice suggest a role for SG in the delivery of proteins into secretory granules and/or directing the secretion of these molecules [2]. It appears that SG interacts with a plethora of molecules, playing a role in the delivery of these components into secretory vesicles and further into their targets via its highly negatively charged GAG chains.Other studies have demonstrated that SG plays a key role in the storage of mast cell proteases and granzyme B and the maturation of secretory granules of mast cells and cytotoxic T-cells [7,8]. Furthermore, SG plays a crucial role in cytotoxic T-cells, as part of a multimolecular complex with perforin and granzyme B, in the delivery of the latter to the target cells during cytotoxic cell-granule-mediated cell death [9]. SG is constitutively secreted but also present on the cell surface of myeloma plasma cells and affects bone mineralization [1...

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Section: Sg Binds To C1q Stalkssupporting

confidence: 82%

“…4D). Decorin, a proteoglycan that has previously been shown to interact with MBL [23], was used as the positive control. We also confirmed that SG bound MBL directly from NHS ( Fig.…”

Section: Sg Binds To C1q and Mblmentioning

confidence: 99%

Serglycin inhibits the classical and lectin pathways of complement via its glycosaminoglycan chains: Implications for multiple myeloma

et al. 2010

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“…[33][34][35][36] It is therefore noteworthy that decorin has been shown to act as a proinflammatory factor and is produced at sites of inflammation. 18,[37][38][39][40][41] In contrast, Decorin, obesity and type 2 diabetes K Bolton et al decorin has also been reported to bind and inhibit the proinflammatory activity of the complement protein C1q 42 and has been hypothesized to antagonize C1q-induced insulin resistance in adipose tissue that is associated with obesity. 16 These observations indicate that decorin may play a role in inflammation associated with obesity in adipose tissue; however, this is likely to be a complex interaction between pro-and anti-inflammatory activities.…”

Section: Discussionmentioning

confidence: 99%

Decorin is a secreted protein associated with obesity and type 2 diabetes

et al. 2008

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Objective: To characterize the expression of the small leucine-rich glycoprotein decorin in adipose tissue. Design: Real-time PCR was used to measure decorin gene expression in adipose tissue from normal glucose tolerant (NGT), impaired glucose tolerant and type 2 diabetic (T2D) Psammomys obesus. Adipose tissue was fractionated to determine which cells were responsible for decorin expression. The location of decorin protein expression in adipose tissue was determined using immunohistochemistry. Real-time PCR was used to measure decorin mRNA levels in human adipose tissue from 16 insulinsensitive, 16 insulin-resistant and 6 T2D human subjects. Circulating plasma decorin concentrations were measured by enzymelinked immunosorbent assay in 145 NGT and 141 T2D human individuals from a large-scale epidemiological study in Mauritius. Results: Decorin mRNA was found to be highly expressed in adipose tissue, and decorin gene expression was significantly higher in visceral than that in subcutaneous adipose tissue depots in both P. obesus and human subjects (P ¼ 0.002 and P ¼ 0.001, respectively). Decorin mRNA was predominantly expressed by stromal/vascular cells of adipose tissue, and decorin protein in adipose tissue was primarily detected adjacent to blood vessels. Circulating plasma decorin levels in humans were elevated by 12% in T2D (P ¼ 0.049) compared to NGT subjects. There was a significant independent correlation between plasma decorin levels and waist-to-hip ratio (WHR, P ¼ 0.024). In male subjects, plasma decorin levels were significantly correlated with WHR (P ¼ 0.006), and fasting and 2-h glucose levels in an oral glucose tolerance test (P ¼ 0.027 and P ¼ 0.001, respectively). Conclusions: Decorin expression in adipose tissue was markedly upregulated in the obese state and may therefore play a role in adipose tissue homeostasis or in pathophysiology associated with obesity.

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“…The proteoglycans decorin and biglycan can inhibit the classic pathway directly through binding and inhibition of C1q, whereas biglycan inhibits the MBL pathway by inactivating MBL (121). Decorin and biglycan show further inhibition of complement by preventing C1q binding to human umbilical vein endothelial cells and U937 cells, with biglycan further able to inhibit C1q-mediated release of inflammatory monocyte chemoattractant peptide-1 and IL-8 from human umbilical vein endothelial cells (121).…”

Section: Complement Proteins Reorganize Intercellular and Extracellulmentioning

confidence: 99%

Cancer and the Complement Cascade

Rutkowski

Sughrue

Kane

et al. 2010

Molecular Cancer Research

229

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Despite significant research on the role of inflammation and immunosurveillance in the immunologic microenvironment of tumors, little attention has been given to the oncogenic capabilities of the complement cascade. The recent finding that complement may contribute to tumor growth suggests an insidious relationship between complement and cancer, especially in light of evidence that complement facilitates cellular proliferation and regeneration. We address the hypothesis that complement proteins promote carcinogenesis and suggest mechanisms by which complement can drive the fundamental features of cancer. Evidence shows that this diverse family of innate immune proteins facilitates dysregulation of mitogenic signaling pathways, sustained cellular proliferation, angiogenesis, insensitivity to apoptosis, invasion and migration, and escape from immunosurveillance. Given that the traditionally held functions for the complement system include innate immunity and cancer defense, our review suggests a new way of thinking about the role of complement proteins in neoplasia.

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Interactions of the Extracellular Matrix Proteoglycans Decorin and Biglycan with C1q and Collectins

Cited by 114 publications

References 31 publications

Serglycin inhibits the classical and lectin pathways of complement via its glycosaminoglycan chains: Implications for multiple myeloma

Serglycin inhibits the classical and lectin pathways of complement via its glycosaminoglycan chains: Implications for multiple myeloma

Decorin is a secreted protein associated with obesity and type 2 diabetes

Cancer and the Complement Cascade

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