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Vol. 291, Issue 3, 1156-1163, December 1999
B, cAMP
Response Element-Binding Protein, and Interleukin-2 Secretion by
Activated Thymocytes1
Department of Pharmacology and Toxicology (A.C.H., N.E.K.) and
Department of Pathology (N.E.K.), Michigan State University, East
Lansing, Michigan
Cannabinol (CBN), an immunosuppressive cannabinoid and ligand for the
peripheral cannabinoid receptor CB2, inhibits the cAMP signaling
cascade in forskolin-stimulated thymocytes. The objective of the
present studies was to further characterize the mechanism of CBN immune
modulation by investigating its effects on interleukin-2 (IL-2)
secretion, cAMP response element (CRE), and 
B DNA binding activity
in phorbol ester (phorbol-12-myristate-13-acetate, PMA) plus calcium
ionophore (PMA/Io)-activated thymocytes. PMA/Io treatment induced CRE
and B DNA binding activity that was attenuated in the presence of
CBN. A concomitant and concentration-related inhibition of IL-2 also
was produced by CBN in PMA/Io-activated thymocytes. PMA/Io induced two
CRE DNA binding complexes, a major complex consisting of a cAMP
response element-binding protein (CREB)-1 homodimer, and a minor
CREB-1/activating transcription factor (ATF)-2 complex. Both CRE
complexes were inhibited by CBN. Conversely, two B DNA binding
complexes were observed, but only one was PMA/Io-inducible. However,
the DNA binding activity of both complexes was diminished in the
presence of CBN. The PMA/Io-inducible B complex was a p65/c-Rel
heterodimer. Analysis of up-stream regulation revealed a decrease in
phosphorylated CREB/ATF nuclear proteins in PMA/Io-activated thymocytes
after CBN treatment. Similarly, CBN prevented the
phosphorylation-dependent degradation of the nuclear factor-B
inhibitory protein IB-
. These results provide a potential link
between the CBN-mediated inhibition of thymocyte function, including
IL-2 production, and the inhibition of two critical transcription
factor families, CREB/ATF and NF-B/Rel.
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