Abstract 1353: Alleviation of sepsis in osteosarcoma-bearing mice via immunomodulatory cytokine interleukin-30 treatment

Abstract

Abstract Background Sepsis, an acute systemic inflammatory response to infection, is the most common cause of patient mortality in intensive care units. Cancer patients are nearly 10 times more susceptible to sepsis than non-cancer patients, and sepsis accounts for 8.5% of all deaths among cancer patients. Current therapeutic strategy to sepsis is antimicrobial therapy, hemodynamic support and adjunctive therapy, and other supportive therapy. Despite recent therapeutic progress, mortality rates remain high in sepsis patients. Here we tested the protective effect of IL-30, a novel cytokine against inflammation-induced liver injury, on sepsis in both normal and tumor-bearing mice. Methods Mice were injected with LPS (∼20 mg/kg) to induce septic shock or underwent cercal ligation and puncture (CLP) to induce polymicrobial sepsis. C3H/He mice were orthotopically inoculated with LM8 cells (1×105) to generate tumors and performed CLP after tumor development. The control or IL30 encoding DNA was administered to tibialis msucles via electroporation. Recombinant mouse IL30, IFN-γ or TNF-α protein was directly administered via injection. Mice were monitored every 6 h for the subsequent 6 days to determine their survival. The concentrations of cytokines in serum were analyzed via Luminex system. The cellular sources of cytokines were analyzed by intracellular flow cytometry. Results IL-30 treatment reduced mortality in both normal and tumor-bearing mice in multiple experimental sepsis models including osteosarcoma bearing mouse model. This reduction in mortality is likely through attenuation of the systemic pro-inflammatory response and increasing of bacteria clearance. Specifically, IL-30 treatment suppressed TNF-α and IFN-γ production and increased IL-10 production in serum induced by LPS. And IL-30 treatment increased the percentage of IL10+ NKT cells and decreased the percentage of IFN-γ+ NKT cells, which were induced by LPS in liver and spleen of C57BL/6 mice. Administering either recombinant IFN-γ or TNF-α impaired the protective function of IL30 against sepsis. Likewise, mice deficient of IL-10 or NKT cells abolished the protective role of IL-30 against sepsis. These results show that the protective effect of IL-30 against sepsis is mediated via augmentation of IL-10 secretion and suppression of abundant IFN-γ production. Interestingly, p-STAT3 was increased, and p-STAT1 was dramatically decreased by IL-30 treatment in spleen of LPS-challenged mice. Therefore, IL-30 may increase IL-10 production via STAT3 activation. Though IL-30 is one of the subunit of IL-27, but its effect on sepsis reduction was independent on IL-27 signaling pathway. Conclusion IL-30 is valuable candidate for prevention and treatment of sepsis via promoting the generation of IL-10-producing NKT cells. These findings reveal the anti-inflammatory role of IL-30 in sepsis. Citation Format: Jun Yan, Abhisek Mitra, Jiemiao Hu, Jeffery J. Cutrera, Xueqing Xia, Lopa Mishra, Shulin Li. Alleviation of sepsis in osteosarcoma-bearing mice via immunomodulatory cytokine interleukin-30 treatment. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1353. doi:10.1158/1538-7445.AM2015-1353