Study on roles of angiostatic factor IP-10 and Mig in atherogenesis

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IFN-inducible protein of 10 kDa (IP-10), IFN-inducible T cell α chemoattractant (I-Tac) and monokine induced by IFN-γ(Mig) are T cell directed CXC chemokines and also anti-angiogenic factors. We investigated roles of IP-10 in intimal neovascularization and atherogenesis in apoE deficient mice fed high cholesterol diet. Intimal neovascularization was evaluated using anti-CD31 Ab and anti-VWF Ab and rarely observed in mice,fed a high cholesterol diet for 30 weeks. We prepared rat anti mouse IP-10 monoclonal antibody (anti-IP-10 mAb) to block the action of IP-10 in apoE deficient mice. Mice were fed a high cholesterol diet from 6 weeks of age and subjected to intra-peritoneal injection of anti-IP-10 mAb (group 1) or PBS (group 2) from 12 weeks to 18 weeks twice a week. Intimal neovascularization was hardly seen in both groups. The mean area of advanced atherosclerotic lesions was similar in both groups. When 6-week-old mice were fed a high cholesterol diet and injected with anti-IP-10 mAb (group 3) or PBS (group 4) for 6 weeks, the mean area of early atherosclerotic lesion of group3 tended to be smaller than that of group 4. These results suggest that IP-10 may play a significant role during the development of early atherosclerotic lesion. However, the number of mice to be studied should be increased to confirm the difference between groups 3 and 4. In addition to animal study, regulation of IP-10, Mig and I-Tac gene expression in cultured endothelial cells was studied. We have reported that a bio-active phospholipid lysophosphatidylcholine (lysoPC) inhibits the interferon (IFN)-γ-induced gene expression of these chemokines in endothelial cells, suggesting immuno-moduratory role of lysoPC. In this project, we elucidated a mechanism responsible for the inhibitory effect of lysoPC : lysoPC inhibits the IFN-γ-induced gene expression of IP-10, Mig and I-Tac at post-transcriptional level