TLR4-mediated activation of mouse macrophages by Korean mistletoe lectin-C (KML-C).
Korean mistletoe lectin (KML-C) is an adjuvant that activates systemic and mucosal immune cells to release cytokines including TNF-alpha, which induces immunity against viruses and cancer cells. Although the immunomodulatory activity of KML-C has been well established, the underlying mechanism of action of KML-C has yet to be explored. When mouse peritoneal macrophages were treated with KML-C, both transcription and translation of TLR4 were upregulated. KML-C-induced TLR4 downstream events were similar to those activated by LPS: the upregulation of interleukin-1 receptor-associated kinase-1 (IRAK1); resulting in macrophage activation and TNF-alpha production. When TLR4 was blocked using a TLR4-specific neutralizing antibody, TNF-alpha production from the macrophages was significantly inhibited. Moreover, TLR4-deficient mouse macrophages treated with KML-C also secreted greatly reduced level of TNF-alpha secretion. Finally, TLR4 molecules were co-precipitated with KML-C, to which agarose beads were conjugated, indicating that those molecules are associated. These data indicate that KML-C activates mouse macrophages to secrete TNF-alpha by interacting with the TLR4 molecule and activating its signaling pathways.
Park
Hong-Jai
HJ
Institute for Biomedical Research, Handong University, Namsong-ri 3, Heunghae-eup, Buk-gu, Pohang, Kyungbuk 791-708, South Korea.
Hong
Ju-ho
JH
Kwon
Hyung-Joon
HJ
Kim
Youngchan
Y
Lee
Kwan-Hee
KH
Kim
Jong-Bae
JB
Song
Seong K
SK
D000276:Adjuvants, Immunologic / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D005260:Female; D053592:Interleukin-1 Receptor-Associated Kinases / Q000378:metabolism; D008262:Macrophage Activation; D017737:Macrophages, Peritoneal / Q000187:drug effects* / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D014784:Mistletoe / Q000276:immunology*; D037121:Plant Lectins / Q000378:metabolism / Q000494:pharmacology*; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015854:Up-Regulation
D000276:Adjuvants, Immunologic; D037121:Plant Lectins; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; D053592:Interleukin-1 Receptor-Associated Kinases; C507769:Irak1 protein, mouse