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.