REGULATION OF INTERLEUKIN-6 (IL-6) EXPRESSION - EVIDENCE FOR A TISSUE-SPECIFIC ROLE OF PROTEIN-KINASE-C

The regulation of IL-6 mRNA expression was studied in human blood mono cytes and in the human epidermoid carcinoma cell line HEp-2. In human monocytes phorbol-12-myristate 13-acetate (PMA) did not induce IL-6 bu t it increased IL-1beta and IL-8 mRNA levels. Furthermore, in monocyte s, protein kinase C (PKC) activation by PMA even reduced IL-1-induced IL-6 mRNA, and IL-1-induced IL-6 synthesis was increased by the PKC in hibitor staurosporine. IL-6 synthesis in HEp-2 cells was induced by IL -1, PMA, and calcium ionophore A 23187 but not by dibutyryl-cAMP. PMA- , but not IL-1-induced IL-6 synthesis in HEp-2 cells was inhibited by staurosporine. PMA pretreatment of HEp-2 cells abolished PMA-induced I L-6 but the IL-1 effect was not reduced. These data indicate that IL-6 can be induced by a PKC-independent pathway in monocytes and HEp-2 ce lls. In monocytes PKC activation does not induce IL-6 and PMA interfer es with the IL-1 effect. Transcription factors known to be involved wi th the regulation of IL-6 expression were studied by gel retardation a ssays. NF-IL-6 and AP-1 activity were constitutively expressed in mono cytes and HEp-2 cells under conditions where IL-6 mRNA was not detecta ble and levels did not change in response to stimulation by IL-1 or PM A. In contrast, NF-kB was increased by both IL-1 and PMA, but only the effect of PMA, and not that of IL-1, was inhibited by staurosporinc. In summary, these results show tissue-specific differences in the regu lation of IL-6 expression. Induction of IL-6 in monocytes is PKC indep endent. In the epithelial cell line HEp-2 IL-6 is inducible by PKC as well as by a PKC-independent pathway.