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PMID:20610799

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Citation

Gorovoy, M, Gaultier, A, Campana, WM, Firestein, GS and Gonias, SL (2010) Inflammatory mediators promote production of shed LRP1/CD91, which regulates cell signaling and cytokine expression by macrophages. J. Leukoc. Biol. 88:769-78

Abstract

LRP1 is a type-1 transmembrane receptor that mediates the endocytosis of diverse ligands. LRP1 β-chain proteolysis results in release of sLRP1 that is present in human plasma. In this study, we show that LPS and IFN-γ induce shedding of LRP1 from RAW 264.7 cells and BMMs in vitro. ADAM17 was principally responsible for the increase in LRP1 shedding. sLRP1 was also increased in vivo in mouse plasma following injection of LPS and in plasma from human patients with RA or SLE. sLRP1, which was purified from human plasma, and full-length LRP1, purified from mouse liver, activated cell signaling when added to cultures of RAW 264.7 cells and BMMs. Robust activation of p38 MAPK and JNK was observed. The IKK-NF-κB pathway was transiently activated. Proteins that bind to the ligand-binding clusters in LRP1 failed to inhibit sLRP1-initiated cell signaling, however an antibody that targets the sLRP1 N terminus was effective. sLRP1 induced expression of regulatory cytokines by RAW 264.7 cells, including TNF-α, MCP-1/CCL2, and IL-10. These results demonstrate that sLRP1 is generated in inflammation and may regulate inflammation by its effects on macrophage physiology.

Links

PubMed PMC2974427 Online version:10.1189/jlb.0410220

Keywords

Adult; Aged; Animals; Arthritis, Rheumatoid/immunology; Arthritis, Rheumatoid/metabolism; Electrophoresis, Polyacrylamide Gel; Enzyme-Linked Immunosorbent Assay; Female; Humans; Inflammation Mediators/immunology; Inflammation Mediators/metabolism; Lupus Erythematosus, Systemic/immunology; Lupus Erythematosus, Systemic/metabolism; Macrophages/immunology; Macrophages/metabolism; Male; Mice; Middle Aged; Polymerase Chain Reaction; Receptors, LDL/immunology; Receptors, LDL/metabolism; Signal Transduction/immunology; Tumor Suppressor Proteins/immunology; Tumor Suppressor Proteins/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

RAT:ADA17

involved_in

GO:0002532: production of molecular mediator involved in inflammatory response

ECO:0000266: sequence orthology evidence used in manual assertion

RGD:731401

P

Seeded From UniProt

complete

MOUSE:ADA17

GO:0002532: production of molecular mediator involved in inflammatory response

ECO:0000314:

P

ADAM17 is the primary mediator in LPS-induced LRP1 shedding. Fig.2

complete
CACAO 3570

MOUSE:ADA17

involved_in

GO:0002532: production of molecular mediator involved in inflammatory response

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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