IL-12/IL-18のマウス扁平上皮癌に対する抗腫瘍効果の検討

Interleukin-12 (IL-12) and interleukin-18 (IL-18) exhibit strong anti-tumor effects, and induce cytokines with many similarities in function, such as induction of IFN- γ production. Concomitant administration of IL-12 and IL-18 may increase the effects. In this study, we used squamous cell carcinoma that spontaneously developed in inbred strain WHT/Ht mice. IL-12 and IL-18 were administered alone or concomitantly to tumor-bearing mice, and the antitumor effects of the cytokines were compared. As a result, the tumor growth was inhibited by IL-12 and IL-18, and prolonged survival. IFN- γ production was also increased. On measurement of cytotoxic activity and NK activity, administration of IL-12 and IL-18 increased the activities. All these effects were stronger in the concomitant administration group than the single administration groups, but body weight decreased in the concomitant administration group. The above findings suggested that the antitumor effects of IL-12 and IL-18 are exerted via T cells and NK cells, which increase IFN- γ production and enhance cellular immunity

Induction of Tissue Factor Expression in Endothelial Cells by Basic Fibroblast Growth Factor and its Modulation by Fenofibric acid

BACKGROUND: Tissue factor (TF), expressed in endothelial cells (ECs) and enriched in human atherosclerotic lesions, acts as a critical initiator of blood coagulation in acute coronary syndrome. Basic fibroblast growth factor (bFGF) induces the proliferation and migration of ECs and plays a role in angiogenesis and restoration of endothelial integrity. As TF is implicated in angiogenesis, we studied the effect of bFGF on TF gene and protein expression. Methods: Human umbilical vein ECs (HUVECs) were exposed to bFGF. TF mRNA was assessed by Northern blot and TF protein was assessed by Western blot. TF promoter activity was assessed by transient transfection assay and transcription factor was identified by electro mobility shift assay. RESULTS: bFGF increased TF mRNA and protein expression in HUVECs. Increased TF mRNA was attenuated by inhibition of extracellular signal-regulated kinase kinase in human ECV304 cells. Transient transfection assays of the human TF promoter-luciferase construct (-786/+121 bp) demonstrated that bFGF induced transcription was dependent on the elements within the -197 to -176 bp relative to the transcription start site of the human TF gene. This region contains NF-κB like binding site. Electro mobility shift assay showed that bFGF increased nuclear translocation or DNA binding of NF-κB transcription factor to TF promoter. Nucleotide substitution to disrupt NF-κB like site reduced bFGF stimulated promoter activity. Fenofibric acid, an agonist ligand for the peroxisome proliferator activated receptor-α, reduced basal and bFGF stimulated TF expression. CONCLUSIONS: These results indicate that bFGF may increase TF production in ECs through activation of transcription at NF-κB binding site, and control coagulation in vessel walls. Fibrate can inhibit TF expression and therefore reduce the thrombogenecity of human atherosclerotic lesions

Chronic beta-adrenergic receptor stimulation enhances the expression of G-Protein coupled receptor kinases, GRK2 and GRK5, in both the heart and peripheral lymphocytes

Background: Enhanced expression of G protein-coupled receptor kinase (GRK) has been reported in failing hearts and in the present study the stability of enhanced GRK mRNA expression, and the correlation between the expression level of GRK mRNA in peripheral lymphocytes and in the heart were both evaluated. Methods and Results: Isoproterenol was injected into rats for 2 weeks, and then GRK5 mRNA was assessed by quantitative reverse transcriptase-palymerase chain reaction. An enhanced expression of cardiac GRK5 mRNA was observed even after 4 weeks of recovery. The isoproterenol-induced increased expression of GRK2 and GRK5 mRNA was equally observed in the heart and lymphocytes, and there was a close correlation between the heart and lymphocytes in the level of expression of each GRK mRNA. Conclusions: The GRK mRNA level is maintained at a high level for a long period without continuous β-adrenergic receptor stimulation. The level in circulating lymphocytes could be used as a surrogate marker to estimate the level of cardiac GRK expression and, presumably, the β-adrenergic receptor function of cardiomyocytes. (Circ J 2005; 69: 987-990