Icariin and its derivative, ICT, exert anti-inflammatory, anti-tumor effects, and modulate myeloid derived suppressive cells (MDSCs) functions.
3, 5,7-trihydroxy-4'-methoxy-8-(3-hydroxy-3-methylbutyl)-flavone (ICT) is a novel derivative of Icariin (ICA), the major active ingredient of Herba Epimedii, a herb used in traditional Chinese and alternative medicine. We previously demonstrated its anti-inflammatory effect in murine innate immune cells and activated human PBMCs. We report herein that ICA or ICT treatment reduces the expression of MRP8/MRP14 and toll-like receptor 4 (TLR4) on human PBMCs. Administration of ICA or ICT inhibited tumor growth in 4T1-Neu tumor-bearing mice and considerably decreased MDSC numbers in the spleen of these mice. Further, we saw a restoration of IFN-γ production by CD8+ T cells in tumor bearing mice when treated with ICA or ICT. ICA and ICT significantly decreased the amounts of nitric oxide and reactive oxygen species in MDSC in vivo. When MDSC were treated in vitro with ICT, we saw a significant reduction in the percent of these cells with concomitant differentiation into dendritic cells and macrophages. Concomitant with this cell type conversion was a down-regulation of IL-10, IL-6 and TNF-α production. Decreased expression of S100A8/9 and inhibition of activation of STAT3 and AKT may in part be responsible for the observed results. In conclusion, our results showed that ICA, and more robustly, ICT, directly modulate MDSC signaling and therefore altered the phenotype and function of these cells, in vitro and in vivo.
Department of Immunology, H. Lee. Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA.
Junmin
J
Zhou
Jinfeng
J
Wu
Xianghong
X
Chen
Nicole
N
Fortenbery
Erika
E
Eksioglu
Krithika N
KN
Kodumudi
Epling-Burnette
EB
Pk
Jingcheng
J
Dong
Julie Y
JY
Djeu
Sheng
S
Wei
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage; D000970:Antineoplastic Agents / Q000008:administration & dosage; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D040501:Calgranulin A / Q000235:genetics / Q000378:metabolism; D040502:Calgranulin B / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D034181:Epimedium / Q000276:immunology; D047309:Flavones / Q000008:administration & dosage; D005419:Flavonoids / Q000008:administration & dosage*; D006801:Humans; D007165:Immunosuppression Therapy; D051379:Mice; D008819:Mice, Nude; D022423:Myeloid Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
C558386:3,5,7-trihydroxy-4'-methoxy-8-(3-hydroxy-3-methylbutyl)flavone; D000893:Anti-Inflammatory Agents; D000970:Antineoplastic Agents; D040501:Calgranulin A; D040502:Calgranulin B; D016207:Cytokines; D047309:Flavones; D005419:Flavonoids; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; C056599:icariin
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