CYTOKINE REGULATION OF INTERLEUKIN-6 GENE-EXPRESSION IN ASTROCYTES INVOLVES ACTIVATION OF AN NF-KAPPA-B-LIKE NUCLEAR-PROTEIN

The cytokines interleukin-1 beta (IL-1-beta) and tumor necrosis factor-alpha (TNF-alpha) induce interleukin-6 (IL-6) gene expression in astrocytes. The molecular mechanism(s) by which these cytokines activate IL-6 expression was examined by transient transfection of the human IL-6 promoter linked to the reporter gene CAT (IL-6-CAT) in primary rat astrocytes. We show that both IL-1-beta and TNF-alpha exert their effects through the IL-6 promoter to increase CAT activity, indicating that the cytokines act at the transcriptional level. Use of deletion mutants revealed that the NF-kappa-B-like binding site is required for cytokine induction of IL-6 promoter activity. The correlary effects of IL-1-beta and TNF-alpha on DNA-binding proteins specific for this element were examined. Treatment of astrocytes with either cytokine leads to a rapid activation (15 min) of a nuclear protein which specifically complexes with the NF-kappa-B-like binding region in the IL-6 promoter. These results suggest that TNF-alpha and IL-1-beta activate IL-6 gene expression in astrocytes by a mechanism(s) involving activation of an NF-kappa-B-like protein.