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IL-12 plays anti-tumor effect by inducing NK cell activation in hepatic carcinoma microenvironment
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Abstract:
Objective:To explore the enhanced anti-tumor effect of IL-12 through inducing NK cell activition in hepatic carcinoma microenviroment. Methods: The hepatic cacinoma HepG2 cells were subcutaneously injected into NOD/SCID mice, and human peripheral blood lymphocytes (PBL) were introperitoneally injected after tumor formation to establish HCC-huPBL tumor-bearing mouse model. The tumor-bearing mice were randomized into IL-12 group and PBS control group. Mice were intratumoral injected with IL-12, and the changes of tumor volume and body weight as well as general conditions of tumor-bearing mice were observed. ELISA assay was performed to examine the expression levels of IL-12 and INF-γ in the microenvironment of hepatic carcinoma tissues in tumor-bearing mice, and the aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels in peripheral blood of mice 30 days after IL-12 intratumoral injection. Immunohistochemistry assay was used to analyze the expressions of NK-activating receptors: NKG2D, NKp44, NKp30, NKp46, and inhibitory NK receptors: KIR2DL3/CD158b and NKG2A/CD159a in hepatic carcinoma microenvironment after IL-12 treatment. Results: On day 12, 18, 24 and 30, the tumor volumes were smaller in the IL-12 group than those in the PBS group (\[594.47±205.51\] vs \[832.10±187.49\] mm3, \[963.61±427.95\] vs \[1 35087±468.23\] mm3, \[1 285.02±368.56\] vs \[1 975.49±655.54\] mm3, \[1 903.64±471.34\] vs \[2 568.77±784.68\] mm3, P<0.05). The expression levels of IL-12 and IFN-γ in the IL-12 group were significantly higher than those in the PBS group (\[2.96±1.02\] vs \[1.35±0.75\] pg/ml, \[12.26±4.11\] vs \[7.81±3.46\] pg/ml, P<005). The serum ALT level significantly increased in the IL-12 group compared to the PBS group on day 7 (\[7385±10.71\] vs \[41.73±13.13\] U/L, P<0.05), and reached a peak at day 14. The expressions of NK-activating receptors NKG2D, NKp44 and NKp30 were statistically higher in the IL-12 group than those in the PBS group (P<005), the expression level of NKp46 showed no significant up-regulation, while the expression levels of NK inhibitory receptors CD158b and CD159a were decreased compared to the PBS group (P<0.05). Conclusion: IL-12 intratumoral injection can up-regulate the expressions of NK-activating receptors, IL-12 and IFN-γ, and down-regulate the NK inhibitory receptors in the hepatic carcinoma mouse model, therefore effectively inhibiting the tumor growth in mouse model.
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Project Supported:
Project supported by the Science Project for Young Scholars from Health Bureau of Fujian Province （No. 2009-2-30），and the Key Project of Science and Technology Bureau of Fujian Province （No. 2008I0012）
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