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: Chen-Si Lin, Mo-Fan Chen, Yu-Shan Wang, Tien-Fu Chuang, Yi-Lun Chiang, Rea-Min Chu
• Journal: Cytokine (Cytokine) Vol. 62 Issue 3 Pg. 352-9 (Jun 2013) ISSN: 1096-0023 [Electronic] England
• PMID: 23579028 (Publication Type: Journal Article)
• Copyright: Copyright © 2013 Elsevier Ltd. All rights reserved.

Chemical References

• Antigens
• Biomarkers, Tumor
• Interleukin-6
• Smad Proteins
• Smad2 Protein
• Smad3 Protein
• Transforming Growth Factor beta

Topics

• Animals
• Antigens (metabolism)
• Biomarkers, Tumor (metabolism)
• Cell Differentiation (drug effects)
• Cell Nucleus (drug effects, metabolism)
• Dendritic Cells (cytology, drug effects, metabolism, pathology)
• Dogs
• Interleukin-6 (pharmacology)
• Lymphocyte Culture Test, Mixed
• Monocytes (pathology)
• Neoplasms (metabolism)
• Phenotype
• Protein Transport (drug effects)
• Signal Transduction (drug effects)
• Smad Proteins (metabolism)
• Smad2 Protein (metabolism)
• Smad3 Protein (metabolism)
• Transforming Growth Factor beta (pharmacology)