Extremely low dose ionizing radiation up-regulates CXC chemokines in normal human fibroblasts

Although the public today could be exposed to X-rays as high as 1 cGy due to diagnostic procedures, the biological effects of this low-dose range have not been well established. We searched through >23,000 transcripts in normal human fibroblasts, HFLIII, using a novel comprehensive expression analysis method. More than 200 genes were up-regulated transiently by 1 cGy of X-rays during the 1-hour period after irradiation. We determined the nucleotide sequence of 10 up-regulated transcripts with the greatest rate of increase in the irradiated HFLIII cells. Three of the 10 transcripts encoded CXC chemokines (CXCL1, CXCL2, and CXCL6). The rest included the transcripts of other secretory products (secretogranin II, thrombospondin type I domain containing 2, amphiregulin, and interleukin-6) and unknown genes. To test the involvement of CXC chemokines in cells irradiated with low doses, we irradiated HFLIII cells with 1 to 20 cGy X-rays and transferred the media from HFLIII culture to two melanoma cell lines characteristic of excessive numbers of the CXC chemokine-specific receptors. The growth of these melanoma lines were significantly stimulated by the medium from HFLIII irradiated at 1 to 5 cGy. Our results indicate that human cells respond to doses of radiation as low as 1 cGy, and mechanisms alternative to those involved in moderate/high-dose studies have to be considered in understanding the biological effects of diagnostic level radiation. In addition, our comprehensive approach using a novel expression profiling method is a powerful strategy to explore biological functions associated with very low levels of toxic agents.