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Vol. 61, Issue 2, 446-454, February 2002
Department of Pharmacology and Toxicology, Michigan State
University, East Lansing, Michigan
It has been demonstrated previously that cannabinol (CBN)
differentially modulates interleukin-2 (IL-2) protein secretion by T cells with a corresponding change in extracellular
signal-regulated kinase activity. The objective of the present studies
was to further investigate the molecular mechanism by which CBN
enhances IL-2 gene expression using the EL4 T cell line. We demonstrate
here that steady-state IL-2 mRNA expression was significantly enhanced by CBN in a concentration-dependent manner in EL4 cells activated with
suboptimal concentrations of phorbol-12-myristate-13-acetate (2-10
nM). Concordantly, a marked increase was observed in nuclear factor of
activated T cells (NF-AT) DNA binding activity to the IL-2 distal NF-AT
site, but not to nuclear factor for immunoglobulin 
chain in B cells
or activator protein 1 motifs. Transient transfection of EL4 cells with
a reporter gene under the control of multiple IL-2 distal NF-AT motifs
exhibited increased transcriptional activity by CBN in suboptimally
activated cells. In addition, the CBN-mediated enhancement of IL-2
protein secretion and the transcriptional activity of the IL-2 distal
NF-AT reporter gene was abrogated by the calcium/calmodulin-dependent
protein kinase inhibitor KN93, but not by the CB2 receptor antagonist
SR144528. Enhancement of IL-2 was also demonstrated with CP55940,
9-tetrahydrocannabinol, and cannabidiol, thus suggesting
that the phenomenon is not unique to CBN. Collectively, these results
suggest that increased IL-2 secretion by CBN is mediated through the
enhancement of IL-2 gene transcription by activation of NF-AT in a
CB1/CB2-independent manner.
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