INTERLEUKIN-1-BETA USES COMMON AND DISTINCT SIGNALING PATHWAYS FOR INDUCTION OF THE INTERLEUKIN-6 AND TUMOR-NECROSIS-FACTOR-ALPHA GENES IN THE HUMAN ASTROCYTOMA CELL-LINE U373

Cytokines are involved in the etiology of different disorders of the C NS. For a better understanding of their pathogenic role, we analyzed s ignal transduction pathways mediating the interleukin (IL)-1 beta-indu ced synthesis of IL-6 and tumor necrosis factor alpha (TNF alpha) in t he human astrocytoma cell line U373 MG. Both protein kinase C and reac tive oxygen intermediates (ROIs) were involved in IL-6 and TNF alpha g ene expression by IL-1 beta. In contrast, protein tyrosine kinases wer e only necessary for expression of the IL-6 gene. Whereas activation o f protein kinase A was able to induce expression of the IL-6 gene, it did not induce TNF alpha gene expression and was not involved in IL-1 beta-induced IL-6 and TNF alpha gene expression. Activation of the tra nscription factor nuclear factor-kappa B by IL-1 beta involved ROIs, w hereas the IL-1 beta-induced activation of the transcription factor AP -1 was mediated via protein kinase C. Our findings provide the basis f or the development of specific drugs for the treatment of disorders of the CNS in which cytokines play a pathogenic role.