Soluble lipopolysaccharide receptor (CD14) is released via two different mechanisms from human monocytes and CD14 transfectants

Bufler, Philip; Stiegler, Gabor; Schuchmann, Marcus; Hess, Sigrun; Krüger, Christian; Stelter, Felix; Eckerskorn, Christoph; Schütt, Christine; Engelmann, Hartmut

doi:10.1002/eji.1830250244

Cited by 114 publications

(103 citation statements)

References 64 publications

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“…Soluble CD14 detected in human sera has been reported to serve as soluble antagonist for monocyte and macrophage activation [17;37]. Soluble CD14 was shown to be released from cell surface by multiple alternative mechanisms including proteolytic processing dependent on MMP12/MMP9 and other MMPs [38], human leukocyte elastase (HLE) [19] and a leukocyte carboxyl/aspartate protease [7]; lipolytic release from the GPI-linker [37] or direct secretion without the GPI moiety [5].…”

Section: Discussionmentioning

confidence: 99%

Soluble hemojuvelin is released by proprotein convertase-mediated cleavage at a conserved polybasic RNRR site

Lin

Nemeth

Goodnough

et al. 2008

Blood Cells, Molecules, and Diseases

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As the principal iron-regulatory hormone, hepcidin plays an important role in systemic iron homeostasis. The regulation of hepcidin expression by iron loading appears to be unexpectedly complex and has attracted much interest. The GPI-linked membrane protein hemojuvelin (GPIhemojuvelin) is an essential upstream regulator of hepcidin expression. A soluble form of hemojuvelin (s-hemojuvelin) exists in blood and acts as antagonist of GPI-hemojuvelin to downregulate hepcidin expression. The release of s-hemojuvelin is negatively regulated by both transferrin-bound iron (holo-Tf) and non-transferrin bound iron (FAC), indicating s-hemojuvelin could be one of the mediators of hepcidin regulation by iron. In this report, we investigate the proteinase involved in the release of s-hemojuvelin and show that s-hemojuvelin is released by a proprotein convertase through the cleavage at a conserved polybasic RNRR site.

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Section: Discussionmentioning

confidence: 99%

Soluble hemojuvelin is released by proprotein convertase-mediated cleavage at a conserved polybasic RNRR site

Lin

Nemeth

Goodnough

et al. 2008

Blood Cells, Molecules, and Diseases

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“…43 In addition to the production of sCD14 by proteolysis of the membrane-bound receptor, monocytic cell lines also secrete sCD14 molecules that never acquire a GPI anchor. 44 Although it is widely accepted that endothelial cells do not express mCD14, early-passage human umbilical vein endothelial cells (HUVECs) have been reported to synthesize and express mCD14 at levels that are capable of supporting LPS-induced cell activation. 45 However, LPS activation of endothelial cells is primarily achieved using sCD14.…”

Section: Toll-like Receptor (Tlr)4 Signalingmentioning

confidence: 99%

Lipopolysaccharide signaling in endothelial cells

Dauphinee

Karsan

2006

Laboratory Investigation

534

433

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Sepsis is the systemic immune response to severe bacterial infection. The innate immune recognition of bacterial and viral products is mediated by a family of transmembrane receptors known as Toll-like receptors (TLRs). In endothelial cells, exposure to lipopolysaccharide (LPS), a major cell wall constituent of Gramnegative bacteria, results in endothelial activation through a receptor complex consisting of TLR4, CD14 and MD2. Recruitment of the adaptor protein myeloid differentiation factor (MyD88) initiates an MyD88-dependent pathway that culminates in the early activation of nuclear factor-jB (NF-jB) and the mitogen-activated protein kinases. In parallel, a MyD88-independent pathway results in a late-phase activation of NF-jB. The outcome is the production of various proinflammatory mediators and ultimately cellular injury, leading to the various vascular sequelae of sepsis. This review will focus on the signaling pathways initiated by LPS binding to the TLR4 receptor in endothelial cells and the coordinated regulation of this pathway.

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“…sCD14 may also be cleaved from the cell surface by a cell-associated phospholipase D, a pathway which has been described for other glycosylphosphatidylinositol-anchored surface molecules such as decay accelerating factor [30]. Bufler et al [31] provided evidence for the existence of at least two mechanisms for the sCD14 production by human monocytes, one protease-dependent and the other(s) protease-independent. However using MonoMac-6 cells or CD14-transfected HL60 and U937 cells the authors could not detect protease-dependent shedding of soluble CD14, suggesting that this mechanism is only relevant in mature cells.…”

mentioning

confidence: 93%

The Myeloid Differentiation Antigen CD14 is N‐ and O‐Glycosylated

Stelter¹,

Pfister²,

Bernheiden³

et al. 1996

European Journal of Biochemistry

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The myeloid differentiation antigen CD14 acts as the major receptor for bacterial lipopolysaccharide (LPS). A soluble form of the protein (sCD14) is present in human serum which functions as a soluble LPS receptor. We have compared the isoform patterns of soluble CD14 derived from human serum and of the recombinant proteins produced by CHO cells transfected with either the wild-type CD14 gene or with a cDNA coding for a truncated protein which lacks the C-terminal 21 amino acids [sCD14-(1-335)-peptide]. Using SDSRAGE, two dominant isoforms (53 and 50 kDa) and two minor forms (46 and 43 kDa) can be detected in serum as well as in the supernatants of both transfectants. sCD14 is a glycoprotein which carries N-and 0-linked carbohydrates. The different isoforms of sCD14-(1-335)-peptide are due to differences in the content of N-linked sugars. However after the removal of N-and 0-linked carbohydrates from serum-and CHO-derived wild-type proteins, two isoforms are still present. These results indicate that N-linked glycosylation contributes to but does not fully explain the different forms of soluble CD14. We further examined whether the mutation of individual N-linked glycosylation sites influences the expression of membrane-bound and soluble CD14 forms and the ability of the membranebound molecule to bind LPS. As with the wild-type proteins, the different isoforms of the soluble mutants are partially due to differences in N-linked glycosylation. A truncated mutant which lacks the two Nterminal glycosylation sites { [Asplg, Asp132]CD14-(1-335)peptide) does not give rise to multiple forms on SDS gels. Like CD14-(I -335)-peptide, this mutant is not expressed on the cell surface suggesting that a smaller isoform present in the wild-type preparations results from proteolytic cleavage of the membrane-bound molecule. N-linked carbohydrates do not seem to be important for the binding of LPS to membrane-bound CD14.

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Soluble lipopolysaccharide receptor (CD14) is released via two different mechanisms from human monocytes and CD14 transfectants

Cited by 114 publications

References 64 publications

Soluble hemojuvelin is released by proprotein convertase-mediated cleavage at a conserved polybasic RNRR site

Soluble hemojuvelin is released by proprotein convertase-mediated cleavage at a conserved polybasic RNRR site

Lipopolysaccharide signaling in endothelial cells

The Myeloid Differentiation Antigen CD14 is N‐ and O‐Glycosylated

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