Human lactoferrin activates NF-kappaB through the Toll-like receptor 4 pathway while it interferes with the lipopolysaccharide-stimulated TLR4 signaling.

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.

• Authors: Ken Ando, Keiichi Hasegawa, Ken-Ichi Shindo, Tomoyasu Furusawa, Tomofumi Fujino, Kiyomi Kikugawa, Hiroyasu Nakano, Osamu Takeuchi, Shizuo Akira, Taishin Akiyama, Jin Gohda, Jun-Ichiro Inoue, Makio Hayakawa
• Journal: The FEBS journal (FEBS J) Vol. 277 Issue 9 Pg. 2051-66 (May 2010) ISSN: 1742-4658 [Electronic] England
• PMID: 20345905 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Lipopolysaccharides
• NF-kappa B
• Tlr4 protein, mouse
• Toll-Like Receptor 4
• Lactoferrin

Topics

• Animals
• Cattle
• Cell Line
• Humans
• Lactoferrin (metabolism)
• Lipopolysaccharides (immunology)
• Mice
• NF-kappa B (metabolism)
• Signal Transduction
• Toll-Like Receptor 4 (deficiency, immunology, metabolism)