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PMID:20345905

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Citation

Ando, K, Hasegawa, K, Shindo, K, Furusawa, T, Fujino, T, Kikugawa, K, Nakano, H, Takeuchi, O, Akira, S, Akiyama, T, Gohda, J, Inoue, J and Hayakawa, M (2010) Human lactoferrin activates NF-kappaB through the Toll-like receptor 4 pathway while it interferes with the lipopolysaccharide-stimulated TLR4 signaling. FEBS J. 277:2051-66

Abstract

Lactoferrin (LF) has been implicated in innate immunity. Here we reveal the signal transduction pathway responsible for human LF (hLF)-triggered nuclear factor-kappaB (NF-kappaB) activation. Endotoxin-depleted hLF induces NF-kappaB activation at physiologically relevant concentrations in the human monocytic leukemia cell line, THP-1, and in mouse embryonic fibroblasts (MEFs). In MEFs, in which both tumor necrosis factor receptor-associated factor 2 (TRAF2) and TRAF5 are deficient, hLF causes NF-kappaB activation at a level comparable to that seen in wild-type MEFs, whereas TRAF6-deficient MEFs show significantly impaired NF-kappaB activation in response to hLF. TRAF6 is known to be indispensable in leading to NF-kappaB activation in myeloid differentiating factor 88 (MyD88)-dependent signaling pathways, while the role of TRAF6 in the MyD88-independent signaling pathway has not been clarified extensively. When we examined the hLF-dependent NF-kappaB activation in MyD88-deficient MEFs, delayed, but remarkable, NF-kappaB activation occurred as a result of the treatment of cells with hLF, indicating that both MyD88-dependent and MyD88-independent pathways are involved. Indeed, hLF fails to activate NF-kappaB in MEFs lacking Toll-like receptor 4 (TLR4), a unique TLR group member that triggers both MyD88-depependent and MyD88-independent signalings. Importantly, the carbohydrate chains from hLF are shown to be responsible for TLR4 activation. Furthermore, we show that lipopolysaccharide-induced cytokine and chemokine production is attenuated by intact hLF but not by the carbohydrate chains from hLF. Thus, we present a novel model concerning the biological function of hLF: hLF induces moderate activation of TLR4-mediated innate immunity through its carbohydrate chains; however, hLF suppresses endotoxemia by interfering with lipopolysaccharide-dependent TLR4 activation, probably through its polypeptide moiety.

Links

PubMed Online version:10.1111/j.1742-4658.2010.07620.x

Keywords

Animals; Cattle; Cell Line; Humans; Lactoferrin/metabolism; Lipopolysaccharides/immunology; Mice; NF-kappa B/metabolism; Signal Transduction; Toll-Like Receptor 4/deficiency; Toll-Like Receptor 4/immunology; Toll-Like Receptor 4/metabolism

Significance

Annotations

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

HUMAN:TRFL

involved_in

GO:0001817: regulation of cytokine production

ECO:0000314: direct assay evidence used in manual assertion

P

  • occurs_in:(CL:0000057)

Seeded From UniProt

complete

HUMAN:TRFL

involved_in

GO:0034145: positive regulation of toll-like receptor 4 signaling pathway

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • occurs_in:(CL:0000057)

Seeded From UniProt

complete

HUMAN:TRFL

involved_in

GO:0032680: regulation of tumor necrosis factor production

ECO:0000314: direct assay evidence used in manual assertion

P

  • occurs_in:(CL:0000057)

Seeded From UniProt

complete

HUMAN:TRFL

involved_in

GO:0031665: negative regulation of lipopolysaccharide-mediated signaling pathway

ECO:0000314: direct assay evidence used in manual assertion

P

  • occurs_in:(CL:0000057)

Seeded From UniProt

complete

HUMAN:TRFL

involved_in

GO:0051092: positive regulation of NF-kappaB transcription factor activity

ECO:0000314: direct assay evidence used in manual assertion

P

  • occurs_in:(CL:0000057)

Seeded From UniProt

complete

HUMAN:TRFL

involved_in

GO:0071902: positive regulation of protein serine/threonine kinase activity

ECO:0000314: direct assay evidence used in manual assertion

P

  • occurs_in:(CL:0000057)

Seeded From UniProt

complete

HUMAN:TRFL

involved_in

GO:0043123: positive regulation of I-kappaB kinase/NF-kappaB signaling

ECO:0000314: direct assay evidence used in manual assertion

P

  • occurs_in:(CL:0000057)

Seeded From UniProt

complete

HUMAN:TRFL

enables

GO:0043539: protein serine/threonine kinase activator activity

ECO:0000314: direct assay evidence used in manual assertion

F

  • occurs_in:(CL:0000057)

Seeded From UniProt

complete

MOUSE:TRAF6

involved_in

GO:0051092: positive regulation of NF-kappaB transcription factor activity

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • occurs_in:(CL:0000057)

Seeded From UniProt

complete

MOUSE:TRAF6

involved_in

GO:0043123: positive regulation of I-kappaB kinase/NF-kappaB signaling

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • occurs_in:(CL:0000057)

Seeded From UniProt

complete

MOUSE:TRAF6

involved_in

GO:0051092: positive regulation of NF-kappaB transcription factor activity

ECO:0000315: mutant phenotype evidence used in manual assertion

P

occurs_in:(CL:0000057)

Seeded From UniProt

complete

MOUSE:TRAF6

involved_in

GO:0043123: positive regulation of I-kappaB kinase/NF-kappaB signaling

ECO:0000315: mutant phenotype evidence used in manual assertion

P

occurs_in:(CL:0000057)

Seeded From UniProt

complete

HUMAN:TRFL

enables

GO:0043539: protein serine/threonine kinase activator activity

ECO:0000314: direct assay evidence used in manual assertion

F

occurs_in:(CL:0000057)

Seeded From UniProt

complete

HUMAN:TRFL

involved_in

GO:0043123: positive regulation of I-kappaB kinase/NF-kappaB signaling

ECO:0000314: direct assay evidence used in manual assertion

P

occurs_in:(CL:0000057)

Seeded From UniProt

complete

HUMAN:TRFL

involved_in

GO:0034145: positive regulation of toll-like receptor 4 signaling pathway

ECO:0000315: mutant phenotype evidence used in manual assertion

P

occurs_in:(CL:0000057)

Seeded From UniProt

complete

HUMAN:TRFL

involved_in

GO:0032680: regulation of tumor necrosis factor production

ECO:0000314: direct assay evidence used in manual assertion

P

occurs_in:(CL:0000057)

Seeded From UniProt

complete

HUMAN:TRFL

involved_in

GO:0031665: negative regulation of lipopolysaccharide-mediated signaling pathway

ECO:0000314: direct assay evidence used in manual assertion

P

occurs_in:(CL:0000057)

Seeded From UniProt

complete

HUMAN:TRFL

involved_in

GO:0001817: regulation of cytokine production

ECO:0000314: direct assay evidence used in manual assertion

P

occurs_in:(CL:0000057)

Seeded From UniProt

complete

HUMAN:TRFL

involved_in

GO:0051092: positive regulation of NF-kappaB transcription factor activity

ECO:0000314: direct assay evidence used in manual assertion

P

occurs_in:(CL:0000057)

Seeded From UniProt

complete

HUMAN:TRFL

involved_in

GO:0071902: positive regulation of protein serine/threonine kinase activity

ECO:0000314: direct assay evidence used in manual assertion

P

occurs_in:(CL:0000057)

Seeded From UniProt

complete

Notes

See also

References

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