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 monocytes and in the human epidermoid carcinoma cell line HEp-2. In human monocytes phorbol-12-myristate 13-acetate (PMA) did not induce IL-6 but it increased IL-1 beta and IL-8 mRNA levels. Furthermore, in monocytes, 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 inhibitor 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 IL-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 cells. In monocytes PKC activation does not induce IL-6 and PMA interferes with the IL-1 effect. Transcription factors known to be involved with the regulation of IL-6 expression were studied by gel retardation assays. NF-IL-6 and AP-1 activity were constitutively expressed in monocytes and HEp-2 cells under conditions where IL-6 mRNA was not detectable and levels did not change in response to stimulation by IL-1 or PMA. 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 staurosporine. In summary, these results show tissue-specific differences in the regulation of IL-6 expression. Induction of IL-6 in monocytes is PKC independent. In the epithelial cell line HEp-2 IL-6 is inducible by PKC as well as by a PKC-independent pathway.
Gross
V
V
Sam and Rose Stein Institute for Research on Aging, University of California San Diego, La Jolla 92093.
Zhang
B
B
Geng
Y
Y
Villiger
P M
PM
Lotz
M
M
D000470:Alkaloids / Q000494:pharmacology; D001483:Base Sequence; D000001:Calcimycin / Q000494:pharmacology; D002294:Carcinoma, Squamous Cell; D004268:DNA-Binding Proteins / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D007375:Interleukin-1 / Q000494:pharmacology; D015850:Interleukin-6 / Q000096:biosynthesis* / Q000235:genetics; D007822:Laryngeal Neoplasms; D008070:Lipopolysaccharides / Q000494:pharmacology; D008969:Molecular Sequence Data; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D009928:Organ Specificity; D016133:Polymerase Chain Reaction; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects; D019311:Staurosporine; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014157:Transcription Factors / Q000378:metabolism; D014407:Tumor Cells, Cultured
D000470:Alkaloids; D004268:DNA-Binding Proteins; D007375:Interleukin-1; D015850:Interleukin-6; D008070:Lipopolysaccharides; D016328:NF-kappa B; D014157:Transcription Factors; D000001:Calcimycin; D011493:Protein Kinase C; D019311:Staurosporine; D013755:Tetradecanoylphorbol Acetate