INDUCTION OF INTERLEUKIN-6 BY IONIZING-RADIATION IN A HUMAN EPITHELIAL-CELL LINE - CONTROL BY CORTICOSTEROIDS

The cutaneous radiation syndrome after therapeutic or accidental expos ure of human skin to ionizing radiation (IR) is accompanied by inflamm atory processes which are controlled partly by proinflammatory cytokin es. Besides tumour necrosis factor (TNF)-alpha and interleukin (IL)1, the pluripotent cytokine IL-6 belongs to the key mediators of inflamma tion. So far, there are no reports about the regulation of IL-6 by IR in epidermal cells. As an in vitro model to study the effects of IR on IL-6 gene expression, we treated the human epithelial HeLa cell line with different single X-ray doses between 1 and 20 Gy. Twenty-four hou rs after irradiation the IL-6 secretion was dose-dependently enhanced as measured by ELISA. At the transcriptional level, a slight increase of IL-6 transcripts was already detectable 1 h after irradiation, with maximum levels at 2 h, and a decline to baseline levels between 8 and 24 h. Addition of the transcriptional inhibitor actinomycin D inhibit ed the inducibility of IL-6 mRNA by TPA and IR. As the IL-6 promoter c ontains multiple binding sites for activated glucocorticoid receptors within the 5' regulatory region, the potential modulation of IL-6 expr ession by the corticosteroids hydrocortisone, dexamethasone and mometa sone furoate was included in our study to modify the radiation-induced stress response. All corticosteroids applied could efficiently downre gulate TPA- or radiation-induced IL-6 expression on both gene expressi on and protein levels. Mometasone furoate, followed by dexamethasone, was found to be most effective at low concentrations (1 nM), whereas h ydrocortisone had to be applied at about 100-fold higher concentration s to achieve comparable inhibition. This experimental model is aimed a t understanding the molecular circuits following IR, and thus to provi de a basis for the treatment of radiation effects in skin.