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PMID:21072211

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Citation

Coudriet, GM, He, J, Trucco, M, Mars, WM and Piganelli, JD (2010) Hepatocyte growth factor modulates interleukin-6 production in bone marrow derived macrophages: implications for inflammatory mediated diseases. PLoS ONE 5:e15384

Abstract

The generation of the pro-inflammatory cytokines IL-6, TNF-α, and IL-1β fuel the acute phase response (APR). To maintain body homeostasis, the increase of inflammatory proteins is resolved by acute phase proteins via presently unknown mechanisms. Hepatocyte growth factor (HGF) is transcribed in response to IL-6. Since IL-6 production promotes the generation of HGF and induces the APR, we posited that accumulating HGF might be a likely candidate for quelling excess inflammation under non-pathological conditions. We sought to assess the role of HGF and how it influences the regulation of inflammation utilizing a well-defined model of inflammatory activation, lipopolysaccharide (LPS)-stimulation of bone marrow derived macrophages (BMM). BMM were isolated from C57BL6 mice and were stimulated with LPS in the presence or absence of HGF. When HGF was present, there was a decrease in production of the pro-inflammatory cytokine IL-6, along with an increase in the anti-inflammatory cytokine IL-10. Altered cytokine production correlated with an increase in phosphorylated GSK3β, increased retention of the phosphorylated NFκB p65 subunit in the cytoplasm, and an enhanced interaction between CBP and phospho-CREB. These changes were a direct result of signaling through the HGF receptor, MET, as effects were reversed in the presence of a selective inhibitor of MET (SU11274) or when using BMM from macrophage-specific conditional MET knockout mice. Combined, these data provide compelling evidence that under normal circumstances, HGF acts to suppress the inflammatory response.

Links

PubMed PMC2970559 Online version:10.1371/journal.pone.0015384

Keywords

Animals; Blotting, Western; Bone Marrow Cells/drug effects; Bone Marrow Cells/metabolism; Cells, Cultured; Cyclic AMP Response Element-Binding Protein/metabolism; Dose-Response Relationship, Drug; Female; Glycogen Synthase Kinase 3/metabolism; Glycogen Synthase Kinase 3 beta; Hepatocyte Growth Factor/pharmacology; Immunoprecipitation; Indoles/pharmacology; Inflammation/metabolism; Interleukin-6/biosynthesis; Lipopolysaccharides/pharmacology; Macrophages/cytology; Macrophages/drug effects; Macrophages/metabolism; Male; Membrane Proteins/metabolism; Mice; Mice, 129 Strain; Mice, Inbred C57BL; Mice, Knockout; Phosphoproteins/metabolism; Phosphorylation/drug effects; Piperazines/pharmacology; Protein Binding/drug effects; Proto-Oncogene Proteins c-met/genetics; Proto-Oncogene Proteins c-met/metabolism; Sulfonamides/pharmacology; Transcription Factor RelA/metabolism

Significance

Annotations

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

MOUSE:IL10

acts_upstream_of_or_within

GO:0035729: cellular response to hepatocyte growth factor stimulus

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:CBP

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

PR:Q01147

F

Seeded From UniProt

complete

MOUSE:CREB1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

PR:P45481

F

Seeded From UniProt

complete

MOUSE:HGF

acts_upstream_of_or_within

GO:0033137: negative regulation of peptidyl-serine phosphorylation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:HGF

acts_upstream_of_or_within

GO:0032733: positive regulation of interleukin-10 production

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:HGF

acts_upstream_of_or_within

GO:0032715: negative regulation of interleukin-6 production

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:HGF

acts_upstream_of_or_within

GO:0050728: negative regulation of inflammatory response

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:HGF

acts_upstream_of_or_within

GO:1902947: regulation of tau-protein kinase activity

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:MET

acts_upstream_of_or_within

GO:0032675: regulation of interleukin-6 production

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:IL6

acts_upstream_of_or_within

GO:0035729: cellular response to hepatocyte growth factor stimulus

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:GSK3B

acts_upstream_of_or_within

GO:0035729: cellular response to hepatocyte growth factor stimulus

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:TF65

acts_upstream_of_or_within

GO:0035729: cellular response to hepatocyte growth factor stimulus

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:CREB1

acts_upstream_of_or_within

GO:0035729: cellular response to hepatocyte growth factor stimulus

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:CBP

acts_upstream_of_or_within

GO:0035729: cellular response to hepatocyte growth factor stimulus

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

Notes

See also

References

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