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Human lactoferrin down‐regulates expression of adhesion molecules via inhibition of MAP kinases and NF‐κB pathways
Author(s) -
Kim Chan Woo,
Kwon Taek Hwan,
Kim Jiyoung
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.2_supplement.304
Subject(s) - chemistry , lactoferrin , cell adhesion molecule , microbiology and biotechnology , umbilical vein , p38 mitogen activated protein kinases , binding site , cell adhesion , kinase , phosphorylation , nf κb , signal transduction , biology , biochemistry , protein kinase a , cell , in vitro
Lactoferrin (Lf) is an iron‐binding glycoprotein and also known as a DNA‐binding protein, which plays roles in a variety of biological processes including anti‐inflammation. We investigated the effects of Lf on TNF‐α‐induced expression of adhesion molecules in human umbilical vein endothelial cells (HUVEC) and on the adhesion of monocytic U937 cells to HUVEC. Lf downregulated TNF‐α‐induced mRNA and protein levels of ICAM‐1 and VCAM‐1 in HUVEC. The promoter region of ICAM‐1 contains a putative LF‐binding site overlapped with a NF‐ κB binding site which is essential for activation of ICAM‐1 gene. Binding of NF‐κB to its consensus binding element was significantly inhibited in nuclear extracts from HUVEC treated with Lf. Lf was competed with NF‐kB for binding to the putative binding site in ICAM‐1 promoter. TNF‐α‐induced activation of ERK1/2 and JNK was inhibited by Lf but p38 was not affected. Phosphorylation of IkB‐α in TNF‐α‐treated HUVECs was significantly reduced by LF, indicating that LF inhibits translocation of NF‐κB into nucleus as well as the binding of the protein to its consensus element. Adhesion of U937 cells to HUVEC was reduced by Lf, probably due to inhibition of cell adhesion molecule expression in HUVEC by Lf. Our results demonstrate that Lf inhibits expression of ICAM‐1 via inhibition of MAP kinase and NF‐κB pathways, suggesting a protective role of Lf in inflammation.