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Vol. 292, Issue 2, 597-605, February 2000
Department of Pharmacology and Toxicology and Department of
Pathology, Michigan State University, East Lansing, Michigan (N.E.K.);
and Department of Biological Sciences, Korea Advanced Institute of
Science and Technology, Taejon, Korea (S.S.Y., K.-H.Y.).
We previously reported that immunosuppressive
cannabinoids inhibited interleukin (IL)-2 steady-state mRNA expression
and secretion by phorbol-12-myristate-13-acetate plus
ionomycin-activated mouse splenocytes and EL4 murine T-cells. Here we
show that inhibition of IL-2 production by cannabinol, a modest
central nervous system-active cannabinoid, is mediated through the
inhibition of IL-2 gene transcription. Moreover, electrophoretic
mobility shift assays demonstrated that cannabinol markedly inhibited
the DNA binding activity of nuclear factor of activated T-cells (NF-AT)
and activator protein-1 (AP-1) in a time- and concentration-dependent
manner in activated EL4 cells. The inhibitory effects produced by
cannabinol on AP-1 DNA binding were quite transient, showing partial
recovery by 240 min after cell activation and no effect on the activity
of a reporter gene under the control of AP-1. Conversely,
cannabinol-mediated inhibition of NF-AT was robust and sustained as
demonstrated by an NF-AT-regulated reporter gene. Collectively, these
results suggest that decreased IL-2 production by cannabinol in EL4
cells is due to the inhibition of transcriptional activation of the IL-2 gene and is mediated, at least in part, through a transient inhibition of AP-1 and a sustained inhibition of NF-AT.
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