2015.01.19,Professor Tian Zhigang Published a paper entitled:“TLR2 controls the development of hepatocellular carcinoma by reducing interleukin-18-mediated immunosuppression” in Cancer Res
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    2015.01.19,Professor Tian Zhigang Published a paper entitled:“TLR2 controls the development of hepatocellular carcinoma by reducing interleukin-18-mediated immunosuppression” in Cancer Res

  • [2015-03-05]
  • Author:Li S, Sun R, Chen Y,Wei H, Tian Z.
    Abstract:Inflammation is thought to be related to tumor development, but the immune mechanisms underlying hepatocellular carcinoma (HCC) are still not well understood. In our study, we found that Toll-like receptor 2 (TLR2) inhibited production of the inflammatory cytokine interleukin-18 (IL-18) and protected mice from diethylnitrosamine (DEN)-induced HCC. Tlr2-/- mice showed a significant increase in HCC progression after DEN treatment along with impaired CD8+ T cell function. Meanwhile, hepatic Ly6Chigh myeloid-derived suppressor cells (MDSCs) were significantly increased in Tlr2-/- mice after 5 months of DEN treatment. Furthermore, MDSCs exhibited higher iNOS expression levels, which could inhibit IFN-γ production and CD8+ T cell proliferation in vitro. Hepatocytes from Tlr2-/- mice produced more mature IL-18 after DEN treatment, which caused accumulation of Ly6ChighIL-18Rα+ MDSCs in the liver. Recombinant IL-18 induced accumulation of Ly6Chigh MDSCs, and hepatocyte-specific silencing of IL-18 in Tlr2-/- mice decreased the proportion of MDSCs, increased the proportion of functional CD8+ T cells, and alleviated HCC progression. Caspase-8 was responsible for IL-18 production in Tlr2-/- mice since Tlr2-/- mice treated with caspase-8 shRNA exhibited decreased IL-18 production. Furthermore, the TLR2 agonist Pam3CSK4 inhibited both caspase-8 and IL-18 expression, decreased Ly6Chigh MDSCs, increased CD8+ T cell function, and promoted HCC regression. Our findings indicate that TLR2 deficiency accelerates IL-18-mediated immunosuppression in hepatocarcinogenesis, and TLR2 activation may alleviate HCC progression by inhibiting IL-18 production. Thus, these findings provide new insights that may be helpful in designing tumor immunotherapy.

     

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