Transcriptional modulation of human IL-6 gene expression by verapamil.
Calcium channel-blocking agents interfere with the initial increase of cytosolic calcium that follows mitogenic stimulation of T lymphocytes. In cultures of mitogen-stimulated PBMC, verapamil also blocked T cell accumulation of cytoplasmic IL-2-encoding mRNA. In sharp contrast, the addition of verapamil to PHA and PMA-stimulated PBMC augmented the mitogen-stimulated increases in nuclear transcription of IL-6-encoding mRNA, steady state levels of IL-6 encoding mRNA, and release of IL-6 bioactivity. These experiments indicated that an increased IL-6 transcriptional rate rather than stabilization of transcripts accounted for the increased cytoplasmic IL-6 mRNA levels and subsequent expression of IL-6 bioactivity. These effects were not produced by nicardipine, another potent calcium channel blocker, or EGTA. We suggest that a non-calcium-dependent, IL-6 regulatory factor, absent or inactive in verapamil-treated cultures, inhibits IL-6 gene activation in mitogen-stimulated PBMC. Failure to express this inhibitory factor would result in IL-6 gene superinduction at a transcriptional level.
Walz
G
G
Charles A. Dana Research Institute, Boston, MA.
Zanker
B
B
Barth
C
C
Wieder
K J
KJ
Clark
S C
SC
Strom
T B
TB
D015152:Blotting, Northern; D002478:Cells, Cultured; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D015850:Interleukin-6 / Q000235:genetics* / Q000494:pharmacology; D010835:Phytohemagglutinins / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects; D014700:Verapamil / Q000494:pharmacology*
D015850:Interleukin-6; D010835:Phytohemagglutinins; D012333:RNA, Messenger; D014700:Verapamil; D013755:Tetradecanoylphorbol Acetate