Delta-tocotrienol suppresses radiation-induced microRNA-30 and protects mice and human CD34+ cells from radiation injury

PLoS One. 2015 Mar 27;10(3):e0122258. doi: 10.1371/journal.pone.0122258. eCollection 2015.

Abstract

We reported that microRNA-30c (miR-30c) plays a key role in radiation-induced human cell damage through an apoptotic pathway. Herein we further evaluated radiation-induced miR-30 expression and mechanisms of delta-tocotrienol (DT3), a radiation countermeasure candidate, for regulating miR-30 in a mouse model and human hematopoietic CD34+ cells. CD2F1 mice were exposed to 0 (control) or 7-12.5 Gy total-body gamma-radiation, and CD34+ cells were irradiated with 0, 2 or 4 Gy of radiation. Single doses of DT3 (75 mg/kg, subcutaneous injection for mice or 2 μM for CD34+ cell culture) were administrated 24 h before irradiation and animal survival was monitored for 30 days. Mouse bone marrow (BM), jejunum, kidney, liver and serum as well as CD34+ cells were collected at 1, 4, 8, 24, 48 or 72 h after irradiation to determine apoptotic markers, pro-inflammatory cytokines interleukin (IL)-1β and IL-6, miR-30, and stress response protein expression. Our results showed that radiation-induced IL-1β release and cell damage are pathological states that lead to an early expression and secretion of miR-30b and miR-30c in mouse tissues and serum and in human CD34+ cells. DT3 suppressed IL-1β and miR-30 expression, protected against radiation-induced apoptosis in mouse and human cells, and increased survival of irradiated mice. Furthermore, an anti-IL-1β antibody downregulated radiation-induced NFκBp65 phosphorylation, inhibited miR-30 expression and protected CD34+ cells from radiation exposure. Knockdown of NFκBp65 by small interfering RNA (siRNA) significantly suppressed radiation-induced miR-30 expression in CD34+ cells. Our data suggest that DT3 protects human and mouse cells from radiation damage may through suppression of IL-1β-induced NFκB/miR-30 signaling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, CD34 / genetics
  • Antigens, CD34 / metabolism
  • Apoptosis / drug effects
  • Cytokines / genetics
  • Cytokines / metabolism
  • Gamma Rays
  • Humans
  • Lymphocytes / drug effects*
  • Lymphocytes / metabolism
  • Lymphocytes / radiation effects
  • Mice
  • MicroRNAs / genetics*
  • MicroRNAs / radiation effects
  • Radiation Injuries / drug therapy*
  • Radiation Injuries / metabolism
  • Radiation Injuries / prevention & control
  • Radiation-Protective Agents / pharmacology
  • Radiation-Protective Agents / therapeutic use*
  • Transcription Factor RelA / genetics
  • Transcription Factor RelA / metabolism
  • Vitamin E / analogs & derivatives*
  • Vitamin E / pharmacology
  • Vitamin E / therapeutic use
  • Vitamins / pharmacology
  • Vitamins / therapeutic use*

Substances

  • Antigens, CD34
  • Cytokines
  • MIRN30 microRNA, human
  • MicroRNAs
  • Radiation-Protective Agents
  • Transcription Factor RelA
  • Vitamins
  • Vitamin E
  • tocotrienol, delta

Grant support

This study was supported by Armed Forces Radiobiology Research Institute intramural grants (RAB2GO and RAB22676) to MX and RAA610 to SPG. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.