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x-Irradiation in Rat Liver: Consequent Upregulation of Hepcidin and Downregulation of Hemojuvelin and Ferroportin-1 Gene Expression¹

¹ From the Department of Radiation Oncology (H.C., F.R., M.R., R.M.H., A.H., C.F.H.) and Department of Internal Medicine, Section of Gastroenterology and Endocrinology (N.S., B.S., J.D., G.R.), University Hospital Goettingen, Robert-Koch-Strasse 40, 37075 Goettingen, Germany. Received January 16, 2006; revision requested March 21; revision received April 7; final version accepted June 7. Supported by grants SFB 402 TP C6, C7, D3, and GRK 335 from the Deutsche Forschungsgemeinschaft. Address correspondence to H.C. (e-mail: hchrist{at}gwdg.de).

Purpose: To prospectively analyze hepcidin, hemojuvelin, and ferroportin-1 expression after x-irradiation of rat liver and isolated rat hepatocytes.

Materials and Methods: The treatment of the rats and this study were approved by the local committee and the public authority on animal welfare. Rat livers in vivo and isolated rat hepatocytes in vitro were irradiated. The total number of rats in this study was 43. RNA extracted from livers (1, 3, 6, 12, 24, and 48 hours after irradiation) and from hepatocytes (1, 3, 6, 12, and 24 hours after irradiation) was analyzed with real-time polymerase chain reaction and Northern blot. Cytokines and prohepcidin in serum of irradiated rats were quantitatively detected with enzyme-linked immunosorbent assay. Sham-irradiated animals served as controls in all experiments. Differences between sham-irradiated and irradiated data groups were tested with analysis of variance and Dunnett post hoc test.

Results: In vivo, a significant radiation-induced increase of hepcidin (P = .034), interleukin (IL) 1ß (P = .008), IL-6 (P < .011), and tumor necrosis factor (TNF-) (P = .047) expression could be detected within the first 48 hours after irradiation. Expression of hemojuvelin (P = .008) and ferroportin-1 (P = .002) was significantly decreased. Serum iron levels were decreased because of irradiation (P < .058); prohepcidin serum levels were increased (P = .05). In rat hepatocytes in vitro, hepcidin RNA levels were significantly downregulated after irradiation (P < .001). Incubation of irradiated hepatocytes with IL-1ß, IL-6, or TNF- led to upregulation of hepcidin expression in vitro up to 6 hours after irradiation, with subsequent significant downregulation for incubation with IL-1ß (P < .001). Hemojuvelin expression behaved in a way opposite to that of hepcidin.

Conclusion: x-Irradiation of the liver induced changes of hepcidin gene expression that are probably induced by acute phase mediators produced within the liver itself.

© RSNA, 2006