Interleukin-37 promotes DMBA/TPA skin cancer through SIGIRR-mediated inhibition of glycolysis in CD103+DC cells.

Interleukin 37 (IL-37), a member of the IL-1 family, is considered a suppressor of innate and adaptive immunity and, hence is a regulator of tumor immunity. However, the specific molecular mechanism and role of IL-37 in skin cancer remain unclear. Here, we report that IL-37b-transgenic mice (IL-37tg) treated with the carcinogenic 7,12-dimethylbenzoanthracene (DMBA)/12-o-tetradecylphorbol-13-acetate (TPA) exhibited enhanced skin cancer and increased tumor burden in the skin by inhibiting the function of CD103+ dendritic cells (DCs). Notably, IL-37 induced rapid phosphorylation of adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK), and via single immunoglobulin IL-1-related receptor (SIGIRR), inhibited the long-term Akt activation. Specifically, by affecting the SIGIRR-AMPK-Akt signaling axis, which is related to the regulation of glycolysis in CD103+DCs, IL-37 inhibited their anti-tumor function. Our results show that a marked correlation between the CD103+DC signature (IRF8, FMS-like tyrosine kinase 3 ligand, CLEC9A, CLNK, XCR1, BATF3, and ZBTB46) and chemokines C-X-C motif chemokine ligand 9, CXCL10, and CD8A in a mouse model with DMBA/TPA-induced skin cancer. In a word, our results highlight that IL-37 as an inhibitor of tumor immune surveillance through modulating CD103+DCs and establishing an important link between metabolism and immunity as a therapeutic target for skin cancer.

Interleukin-37 promotes colitis-associated carcinogenesis via SIGIRR-mediated cytotoxic T cells dysfunction.

Interleukin-37b (hereafter called IL-37) was identified as fundamental inhibitor of natural and acquired immunity. The molecular mechanism and function of IL-37 in colorectal cancer (CRC) has been elusive. Here, we found that IL-37 transgenic (IL-37tg) mice were highly susceptible to colitis-associated colorectal cancer (CAC) and suffered from dramatically increased tumor burdens in colon. Nevertheless, IL-37 is dispensable for intestinal mutagenesis, and CRC cell proliferation, apoptosis, and migration. Notably, IL-37 dampened protective cytotoxic T cell-mediated immunity in CAC and B16-OVA models. CD8+ T cell dysfunction is defined by reduced retention and activation as well as failure to proliferate and produce cytotoxic cytokines in IL-37tg mice, enabling tumor evasion of immune surveillance. The dysfunction led by IL-37 antagonizes IL-18-induced proliferation and effector function of CD8+ T cells, which was dependent on SIGIRR (single immunoglobulin interleukin-1 receptor-related protein). Finally, we observed that IL-37 levels were significantly increased in CRC patients, and positively correlated with serum CRC biomarker CEA levels, but negatively correlated with the CD8+ T cell infiltration in CRC patients. Our findings highlight the role of IL-37 in harnessing antitumor immunity by inactivation of cytotoxic T cells and establish a new defined inhibitory factor IL-37/SIGIRR in cancer-immunity cycle as therapeutic targets in CRC.

[Effect of acupuncture on target action of ligustrazine in treatment of toxic deafness induced by gentamicin in guinea pigs].

OBJECTIVE: To explore an effective method for treating Gentamicin-induced deafness and the mechanism. METHODS: Guinea pigs were randomly divided into 5 groups: normal control group (group A), model group (group B), Ligustrazine group (group C), acupuncture group (group D) and Ligustrazine plus acupuncture group (group E). The group C, D and E were treated respectively by simple Ligustrazine, simple acupuncture at "Tinggong" (SI 19), "Yifeng" (TE 17), and "Waiguan" (TE 5), and Ligustrazine plus acupuncture. Ten days later, the auditory brainstem response (ABR) thresholds for the wave III , apoptosis and expressions of Bcl-2 and Bax proteins in the organ of Corti of the guinea pig were detected. RESULTS: In the group E, the ABR threshold was significantly lower than that in the group C (P<0.05), and apoptotic cells, the expression of Bax protein and the ratio of Bax/Bcl-2 were lower than those in the group C and D in the organ of Corti, and Bcl-2 protein expression was increased. CONCLUSION: Acupuncture at "Tinggong" (SI 19), "Yifeng" (TE 17), and "Waiguan" (TE 5) has a certain target-synergistic action on Ligustrazine and can increase therapeutic effect of Ligustrazine on Gentamicin-induced deafness, which are possible related with the inhibition of apoptosis, down-regulation of Bax expression and up-regulation of Bcl-2 expression.