Dioscorin isolated from Dioscorea alata activates TLR4-signaling pathways and induces cytokine expression in macrophages.
The Toll-like receptor 4 (TLR4)-signaling pathway is crucial for activating both innate and adaptive immunity. TLR4 is a promising molecular target for immune-modulating drugs, and TLR4 agonists are of therapeutic potential for treating immune diseases and cancers. Several medicinal herb-derived components have recently been reported to act via TLR4-dependent pathways, suggesting that medicinal plants are potential resources for identifying TLR4 activators. We have applied a screening procedure to systematically identify herbal constituents that activate TLR4. To exclude possible LPS contamination in these plant-derived components, a LPS inhibitor, polymyxin B, was added during screening. One of the plant components we identified from the screening was dioscorin, the glycoprotein isolated from Dioscorea alata. It induced TLR4-downstream cytokine expression in bone marrow cells isolated from TLR4-functional C3H/HeN mice but not from TLR4-defective C3H/HeJ mice. Dioscorin also stimulated multiple signaling molecules (NF-kappaB, ERK, JNK, and p38) and induced the expression of cytokines (TNF-alpha, IL-1beta, and IL-6) in murine RAW 264.7 macrophages. Furthermore, the ERK, p38, JNK, and NF-kappaB-mediated pathways are all involved in dioscorin-mediated TNF-alpha production. In summary, our results demonstrate that dioscorin is a novel TLR4 activator and induces macrophage activation via typical TLR4-signaling pathways.
Fu
Shu-Ling
SL
Institute of Traditional Medicine, National Yang-Ming University, 155, Sec.2, Li-Nong St., Taipei 11221, Taiwan. slfu@ym.edu.tw
Hsu
Ya-Hui
YH
Lee
Pei-Yeh
PY
Hou
Wen-Chi
WC
Hung
Ling-Chien
LC
Lin
Chao-Hsiung
CH
Chen
Chiu-Ming
CM
Huang
Yu-Jing
YJ
D000818:Animals; D001854:Bone Marrow Cells / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism*; D027742:Dioscorea / Q000737:chemistry*; D006023:Glycoproteins / Q000302:isolation & purification / Q000494:pharmacology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000502:physiology; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D010936:Plant Extracts / Q000302:isolation & purification / Q000494:pharmacology; D011112:Polymyxin B / Q000494:pharmacology; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000819:agonists / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D016207:Cytokines; D006023:Glycoproteins; D008070:Lipopolysaccharides; D016328:NF-kappa B; D010936:Plant Extracts; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; D048031:JNK Mitogen-Activated Protein Kinases; D011112:Polymyxin B