Differential regulation of interleukin-6 expression in human fibroblasts by tumor necrosis factor-alpha and lymphotoxin.
The treatment of human diploid fibroblasts with tumor necrosis factor (TNF)-alpha and with lymphotoxin (LT) is associated with induction of interleukin-6 (IL-6) transcripts with TNF-alpha being 10-fold more potent than LT. Here we report on the TNF-alpha/LT-induced signaling mechanisms responsible for the regulation of IL-6 gene expression in these cells. Run-on assays demonstrated that both TNF-alpha and LT increase IL-6 mRNA levels by transcriptional activation of this gene. Stability studies of IL-6 transcripts in fibroblasts showed that TNF-alpha delayed IL-6 mRNA decay but not LT. The induction of IL-6 transcripts by TNF-alpha and LT was not inhibited by the isoquinoline sulfonamide derivative H7. Similarly, depletion of protein kinase C (PKC) by 12-O-tetradecanoyl-phorbol 13-acetate (TPA) did not change the ability of TNF-alpha and LT to induce IL-6 transcripts, demonstrating that stimulation by these agents may not be mediated by activation of PKC. Stimulation of IL-6 transcripts in fibroblasts did also not require new protein synthesis as exposure to the protein synthesis inhibitor cycloheximide (CHX) enhanced accumulation of IL-6 mRNA in the presence or absence of TNF-alpha or LT.
Mantovani
L
L
Albert-Ludwigs-Universität Freiburg, Department of Hematology and Oncology, FRG.
Henschler
R
R
Brach
M A
MA
Wieser
R
R
Lübbert
M
M
Lindemann
A
A
Mertelsmann
R H
RH
Herrmann
F
F
D002478:Cells, Cultured; D005347:Fibroblasts / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis* / Q000235:genetics; D007700:Kinetics; D008233:Lymphotoxin-alpha / Q000502:physiology*; D014176:Protein Biosynthesis; D011493:Protein Kinase C / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D013997:Time Factors; D014158:Transcription, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
D015850:Interleukin-6; D008233:Lymphotoxin-alpha; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D011493:Protein Kinase C