| Objective: To explore the significance of interleukin-18(IL-18) and interleukin-18 binding protein(IL-18BP) in the development,transfer and treatment of human hepatic carcinoma,we find the interrelationship between IL-18/IL-18 BP and matrix in liver as well as that between IL-18/IL-18 BP and blood vessel through clinical and animal experiments.Method: Plasma levels of IL-18,IL-18 BP and vascular endothelial growth factor( VEGF) were measured in 66 patients with PHC,23 patients with non-cancerous liver lesions and 30 healthy controls by ELISA. The correlation of serum IL-18,IL-18 BP and VEGF levels before and after surgery were analyzed.SMMC7721 human hepatoma cells were inoculated subcutaneously into nude mice. After tumor formation, The 20 mice were randomly divided into two groups, The nude mice of Experimental group received intraperitoneally injected IL-18 treatment every day and control group mice daily injections of saline, continuous treatment for 30 days. At the end of 30 consecutive days after treatment, all nude mice were killed and their tumor were taken and kept for further test. The expression and distribution of IL-18,IL-18 BP,VEGF and Matrix metalloproteinases(MMPs) in carcinogenic mice and healthy controls were detected by SP Immunohistochemistry.Results:1. Plasma levels of IL-18,IL-18 BP and VEGF in patients with PHC and non-cancerous liver lesions were higher than healthy controls before and after operation(P<0.05).In the groups of PHC and non-cancerous liver lesions, patients with cirrhotic splenomegaly had higher plasma levels of IL-18BP( P<0.05), patients with liver dysfunction had higher plasma levels of IL-18(P<0.05).Moreover, in the two groups, a significantly positive correlation between serum IL-18 and IL18 BP levels was found before operation(r=0.58, r=0.526,P<0.05),meanwhile, plasma level of IL-18 BP was positive correlation with cirrhotic splenomegaly(r=0.559,P<0.05). After operation, VEGF and IL-18 BP levels were both elevated.,but IL-18 level was in according with the liver function.2. To observe MMPs and VEGF in carcinogenic mice and healthy controls by Immunohistochemical technique:IL-18 was found to suppress expression of MMP2, MMP2 in the experimental group was more lower than control group and healthy controls(F=93.715,P<0.01). Also, IL-18 could decrease expression of VEGF and elevate expression of MMP3 and MMP9.In the experimental group and control group, significantly positive correlations between serum IL-18 and IL-18 BP levels were both found(r=0.58, r=0.526,P<0.05),there was also a mutual relationship between MMPs and other cytokines,as well as among different types of MMPs.Conclusion:1. Tumor microenvironment can stimulate immune cells secrete IL-18. IL-18 may be metabolized by liver and excreted by cholecyst.Serum level of IL-18 is directly affected by the state of live function,it can be used as a evaluation index of tumor prognosis. In vivo tumor microenvironment, IL-18 have inhibition to VEGF, can inhibit angiogenesis and tumorigenesis. IL-18 may different effect on different types of MMPs, this may also relate to the roles of different environments, especially in tumor. 2.IL-18 BP may not only be affected by the level of IL-18, but also stimulate MMP3/MMP9,still have synergy with VEGF in angiogenesis to promote the development and metastasis of PHC.3.Though IL-18 and IL-18 BP are secreted in different parts of lesions,but the stimulation of lesions can promote the secretion of serum IL-18 and IL-18 BP at the same time.IL-18 and IL-18 BP have close connection in both serum and organization. |
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