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PMID:21072211
| 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 | ||
|
enables |
GO:0005515: protein binding |
ECO:0000353: physical interaction evidence used in manual assertion |
PR:Q01147 |
F |
Seeded From UniProt |
complete | ||
|
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 | ||
|
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 | |||
|
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 | |||
|
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 | |||
|
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 | |||
|
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 | |||
|
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
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