title: Gamma-tocotrienol, a radiation prophylaxis agent, induces high levels of granulocyte colony-stimulating factor.
abstract: Gamma-tocotrienol (GT3), a promising radioprotectant, is shown to protect CD2F1 mice from radiation-induced neutropenia and thrombocytopenia when given 24h prior to total-body irradiation. GT3 also is shown to increase white blood cells (WBC) and absolute neutrophil counts (ANC) transiently in peripheral blood. We hypothesized that increases in WBC and ANC may involve stimulation of hematopoiesis possibly by cytokines and growth factors. To evaluate the effects of GT3 on hematopoietic system, we measured various cytokines, chemokines and growth factors by cytokine array and Bio-Plex assays. Both showed strong induction of various cytokines and chemokines. GT3 treatment resulted in significant increases in G-CSF, IL-1α, IL-1β, IL-6, IL-12p70, IL-17, MIP-1α, and KC levels. G-CSF levels increased markedly within 12-24h after administration (5441 pg/ml in GT3-treated groups compared to 17 pg/ml in vehicle control). Most of these cytokine levels were elevated in the presence or absence of radiation. Time-course analysis of G-CSF and IL-6 induction showed that both cytokines were induced transiently after GT3 administration, and returned to normal levels by 48 h post-administration. For G-CSF, the peak was observed between 12 and 24h post-administration of GT3; however, the highest levels of IL-6 were obtained between 6 and 12h. These results demonstrate that GT3 induced high levels of G-CSF and other inflammatory cytokines and chemokines within 24h after administration. Survival studies reported showed that the most efficacious time for administering GT3 was 24h prior to irradiation, possibly because it induced key hematopoietic cytokines in that time window. These results also suggest a possible role of GT3-induced G-CSF stimulation in protecting mice from radiation-induced neutropenia and thrombocytopenia.
authors.affiliation: Armed Forces Radiobiology Research Institute, USUHS, Bethesda, MD 20889-5603, United States.
authors.forename: Shilpa S
authors.initials: SS
authors.lastname: Kulkarni
authors.forename: Lynnette H
authors.initials: LH
authors.lastname: Cary
authors.forename: Kristen
authors.initials: K
authors.lastname: Gambles
authors.forename: Martin
authors.initials: M
authors.lastname: Hauer-Jensen
authors.forename: K Sree
authors.initials: KS
authors.lastname: Kumar
authors.forename: Sanchita P
authors.initials: SP
authors.lastname: Ghosh
mesh_terms: D000818:Animals; D002839:Chromans / Q000494:pharmacology*; D016207:Cytokines / Q000097:blood; D005720:Gamma Rays / Q000009:adverse effects; D005786:Gene Expression Regulation / Q000187:drug effects; D016179:Granulocyte Colony-Stimulating Factor / Q000097:blood* / Q000378:metabolism; D008297:Male; D051379:Mice; D011837:Radiation-Protective Agents / Q000494:pharmacology*; D014810:Vitamin E / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D002839:Chromans; D016207:Cytokines; D011837:Radiation-Protective Agents; D014810:Vitamin E; D016179:Granulocyte Colony-Stimulating Factor; C013649:plastochromanol 8