Induction of cytokines by radioprotective tocopherol analogs.

Tocols are a family of eight isomers consisting of four tocopherols and four tocotrienols that exist in four isomeric forms: alpha (alpha), beta (beta), gamma (gamma), and delta (delta). Recently, tocols were found to have important and unique biological effects on nutrition and health other than antioxidant properties and are, therefore, now receiving increased attention. We have demonstrated the radioprotective efficacy of various tocol analogs and some of their esters. Three forms of tocols - alpha-tocopherol, alpha-tocopherol succinate, and gamma-tocotrienol - significantly protected mice against lethal gamma irradiation when administered subcutaneously 24 h before irradiation. The radioprotective effects of tocols on survival were associated with peripheral blood cell recovery after radiation induced cytopenia. Hematopoietic cytokines are known to promote the proliferation and differentiation of blood cell progenitors. Therefore, we hypothesized that peripheral blood cell recovery is preceded by hematopoietic cytokine induction. To test this hypothesis and compare the various radioprotective and non-radioprotective analogs, we measured serum cytokines using a sandwich ELISA, Luminex, and cytokine array in mice treated with various tocols (alpha-tocopherol succinate, alpha-tocopherol, delta-tocopherol, gamma- tocopherol, gamma-tocotrienol, and tocopherol acetate). Among the serum cytokines measured, ELISA and Luminex studies indicated that alpha-tocopherol, alpha-tocopherol succinate, and gamma-tocotrienol increased G-CSF levels in mice. Alpha-tocopherol succinate was most effective in stimulating G-CSF. IL-6 was detected by Luminex in sera samples from mice treated with the above three analogs. The results of the cytokine array suggest that other cytokines and chemokines in addition to G-CSF and IL-6 are induced. Since G-CSF, IL-6, and certain chemokines are important hematopoietic factors, these results support our hypothesis that the protection of mice from radiation-induced hematopoietic death is mediated by cytokines and chemokines. These studies may indicate that alpha-tocopherol succinate can be used as an adjunct in cancer chemotherapy, where neutropenia is a serious problem with threatening infectious complications.