作 者:Li S, Sun R, Chen Y, Wei H, Tian Z.
Abstract：In?ammation 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 signi?cant 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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