TY - JOUR
T1 - Gamma-tocotrienol, a radiation prophylaxis agent, induces high levels of granulocyte colony-stimulating factor
AU - Kulkarni, Shilpa S.
AU - Cary, Lynnette H.
AU - Gambles, Kristen
AU - Hauer-Jensen, Martin
AU - Kumar, K. Sree
AU - Ghosh, Sanchita P.
N1 - Funding Information:
Authors would like to thank Kevin Hieber for technical help and Mark Whitnall for critically reading the manuscript. This work was supported by the US Department of Defense, Defense Threat Reduction Agency grant H.10027_07_AR_R , administered by The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc. SK and LC are affiliated with The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., 6720A Rockledge Drive, suite 100, Bethesda, MD 20817.
PY - 2012/12
Y1 - 2012/12
N2 - Gamma-tocotrienol (GT3), a promising radioprotectant, is shown to protect CD2F1 mice from radiation-induced neutropenia and thrombocytopenia when given 24 h 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 12-24 h 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 24 h post-administration of GT3; however, the highest levels of IL-6 were obtained between 6 and 12 h. These results demonstrate that GT3 induced high levels of G-CSF and other inflammatory cytokines and chemokines within 24 h after administration. Survival studies reported showed that the most efficacious time for administering GT3 was 24 h 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.
AB - Gamma-tocotrienol (GT3), a promising radioprotectant, is shown to protect CD2F1 mice from radiation-induced neutropenia and thrombocytopenia when given 24 h 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 12-24 h 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 24 h post-administration of GT3; however, the highest levels of IL-6 were obtained between 6 and 12 h. These results demonstrate that GT3 induced high levels of G-CSF and other inflammatory cytokines and chemokines within 24 h after administration. Survival studies reported showed that the most efficacious time for administering GT3 was 24 h 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.
KW - Cytokines
KW - G-CSF
KW - Gamma-tocotrienol
KW - IL-6
KW - KC
KW - Radiation
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U2 - 10.1016/j.intimp.2012.09.001
DO - 10.1016/j.intimp.2012.09.001
M3 - Article
C2 - 23000517
AN - SCOPUS:84867090918
SN - 1567-5769
VL - 14
SP - 495
EP - 503
JO - International Immunopharmacology
JF - International Immunopharmacology
IS - 4
ER -