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Published online before print October 13, 2006

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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.0306224

Received for publication March 28, 2006.
Revised September 6, 2006.
Accepted for publication September 11, 2006.

Article

Transcriptional regulation of the cannabinoid receptor type 1 gene in T cells by cannabinoids

Christine Börner ^*, Volker Höllt ^*, Walter Sebald , and Jürgen Kraus ^*@

*Department of Pharmacology and Toxicology, University of Magdeburg, Magdeburg, Germany; and Physiologische Chemie II (Biozentrum), University of Würzburg, Würzburg, Germany

^@ To whom correspondence should be addressed. E-mail: juergen.kraus{at}medizin.uni-magdeburg.de.

	Abstract

Effects of cannabinoids (CBs) are mediated by two types of receptors, CB1 and CB2. In this report, we investigated whether CBs regulate gene expression of their cognate receptors in T cells and studied underlying mechanisms in CD4⁺ Jurkat T cells. Transcription of the CB1 gene was strongly induced in response to -9-tetrahydrocannabinol (THC), whereas the CB2 gene was not regulated. The induction of CB1 gene expression is mediated by CB2 receptors only, as demonstrated by using the CB1 and CB2 agonists R(+)-methanandamide and JWH 015, respectively, and combinations of THC plus CB1- and CB2-specific antagonists. After activation of CB2 receptors, the transcription factor STAT5 is phosphorylated. STAT5 then transactivates IL-4. Induction of IL-4 mRNA as well as IL-4 protein release from the cells are necessary for the following induction of the CB1 gene. This was demonstrated by using decoy oligonucleotides against STAT5, which blocked IL-4 and CB1 mRNA induction, and by using the IL-4 receptor antagonist IL-4 [R121D,Y124D], which blocked the up-regulation of CB1 gene transcription. Transactivation of the CB1 gene in response to IL-4 is then mediated by the transcription factor STAT6, as shown by using decoy oligonucleotides against STAT6. An increase in CB1-mediated phosphorylation of MAPK in cells prestimulated with CB2-specific agonists suggests up-regulation of functional CB1 receptor proteins. In summary, up-regulation of CB1 in T lymphocytes in response to CBs themselves may facilitate or enhance the various immunomodulatory effects related to CBs.

Key Words: interleukin-4 • STAT • IFN- • gene regulation

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				C. Borner, A. Bedini, V. Hollt, and J. Kraus Analysis of Promoter Regions Regulating Basal and Interleukin-4-Inducible Expression of the Human CB1 Receptor Gene in T Lymphocytes Mol. Pharmacol., March 1, 2008; 73(3): 1013 - 1019. [Abstract] [Full Text] [PDF]