title: IL-6 restores dendritic cell maturation inhibited by tumor-derived TGF-β through interfering Smad 2/3 nuclear translocation.
abstract: We previously found, in a canine transferable tumor model, that high concentration of IL-6 produced by tumor-infiltrating lymphocytes effectively restores the MHC expression of the tumor cells and T-cell activation inhibited by tumor-derived TGF-β. This tumor also significantly suppresses monocyte-derived dendritic cells (DCs) differentiation and the functions of differentiated DCs with unknown mechanisms. In this study, we have demonstrated that a strong reaction of IL-6 was present to neutralize TGF-β-down-regulated surface marker expression on DCs (MHC II, CD1a, CD40, CD80, CD83, CD86), TGF-β-hampered DC functions and DC-associated T-cell activation. Western blotting and confocal microscopy results indicated that the presence of IL-6 markedly decreased the nuclear concentration of a TGF-β signaling transducer, Smad 2/3. In addition, while Smad 7 is a potent molecule inhibiting Smad 2/3 nuclear translocation, no significant increase in Smad 7 gene expression upon addition of IL-6 in TGF-β-pretreated DCs was detected, which suggested that the blockage of Smad 2/3 nuclear translocation by IL-6 did not occur through a Smad 7-inhibitory mechanism. In conclusion, IL-6 inhibited TGF-β signaling and concomitantly antagonized the suppression activities of TGF-β on DC maturation and activity. This study enables further understandings of host/cancer interactions an also provide hints facilitating improvements of DC-based cancer immunotherapy.
authors.affiliation: Department of Veterinary Medicine, School of Veterinary Medicine, National Taiwan University, Taiwan, ROC. cslin100@ntu.edu.tw
authors.forename: Chen-Si
authors.initials: CS
authors.lastname: Lin
authors.forename: Mo-Fan
authors.initials: MF
authors.lastname: Chen
authors.forename: Yu-Shan
authors.initials: YS
authors.lastname: Wang
authors.forename: Tien-Fu
authors.initials: TF
authors.lastname: Chuang
authors.forename: Yi-Lun
authors.initials: YL
authors.lastname: Chiang
authors.forename: Rea-Min
authors.initials: RM
authors.lastname: Chu
mesh_terms: D000818:Animals; D000941:Antigens / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects*; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism*; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D004285:Dogs; D015850:Interleukin-6 / Q000494:pharmacology*; D007959:Lymphocyte Culture Test, Mixed; D009000:Monocytes / Q000473:pathology; D009369:Neoplasms / Q000378:metabolism*; D010641:Phenotype; D021381:Protein Transport / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D051785:Smad Proteins / Q000378:metabolism*; D051899:Smad2 Protein / Q000378:metabolism; D051900:Smad3 Protein / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
chemical_list: D000941:Antigens; D014408:Biomarkers, Tumor; D015850:Interleukin-6; D051785:Smad Proteins; D051899:Smad2 Protein; D051900:Smad3 Protein; D016212:Transforming Growth Factor beta