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Molecular Pharmacology

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Research ArticleArticle

Analysis of Promoter Regions Regulating Basal and Interleukin-4-Inducible Expression of the Human CB1 Receptor Gene in T Lymphocytes

Christine Börner, Andrea Bedini, Volker Höllt and Jürgen Kraus
Molecular Pharmacology March 2008, 73 (3) 1013-1019; DOI: https://doi.org/10.1124/mol.107.042945
Christine Börner
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Andrea Bedini
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Volker Höllt
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Jürgen Kraus
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Abstract

The majority of effects of cannabinoids are mediated by the two receptors CB1 and CB2. In addition to neuronal cells, CB1 receptors are expressed in T lymphocytes, in which they are involved in cannabinoid-induced T helper cell biasing. Although basally expressed only weakly in T cells, CB1 receptors are up-regulated in these cells by stimuli such as cannabinoids themselves. This effect is mediated by interleukin-4. In this study, we investigated basal and interleukin-4-inducible expression of the CB1 gene in T lymphocytes. In a promoter analysis, two regions [nucleotides (nts) -3086 to -2490 and nts -1950 to -1653] were identified, which suppress basal transcription of the gene in Jurkat T cells, whereas the region between nts -648 and -559 enhanced basal CB1 transcription. Interleukin-4 markedly induced transcription of CB1 in Jurkat cells and primary human T cells. Experiments using transcription factor decoy oligonucleotides demonstrated that STAT6 mediates regulation of the gene by interleukin-4. Using reporter gene assays and the transcription factor decoy oligonucleotide approach, a binding site for STAT6 was identified at nt -2769 on the human CB1 gene promoter. Interleukin-4 also caused up-regulation of functional CB1 receptor proteins. In interleukin-4 pretreated, but not in naive Jurkat cells, the CB1 agonist R(+)-methanandamide caused a significant inhibition of forskolin-induced cAMP formation. This effect was blocked by the CB1-selective antagonists N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (AM251) and 1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-4-mo rpholinyl-1H-pyrazole-3-carboxamide (AM281). Taken together, these data show that CB1 receptors are expressed and up-regulated by interleukin-4 in T lymphocytes, which enables CB1-mediated communication to cells of other systems, such as neuronal cells.

Footnotes

  • This study was supported by grants from the German Bundesministerium für Bildung und Forschung, Förderkennzeichen 01ZZ0407 (to C.B.).

  • ABBREVIATIONS: IL, interleukin; AM630, 6-iodo-2-methyl-1-[2-(4-morpholinyl)ethyl]-1H-indol-3-yl(4-methoxyphenyl)methanone; CAT, chloramphenicol acetyl transferase; tk, herpes simplex thymidine kinase; PCR, polymerase chain reaction; RT-PCR, reverse transcription-polymerase chain reaction; STAT, signal transducer and activator of transcription; AM251, N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide; AM281, 1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-4-mo rpholinyl-1H-pyrazole-3-carboxamide; nt, nucleotide(s); kb, kilobase(s); ELISA, enzyme-linked immunosorbent assay; bp, base pair.

    • Received October 25, 2007.
    • Accepted December 21, 2007.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 73 (3)
Molecular Pharmacology
Vol. 73, Issue 3
1 Mar 2008
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Research ArticleArticle

Analysis of Promoter Regions Regulating Basal and Interleukin-4-Inducible Expression of the Human CB1 Receptor Gene in T Lymphocytes

Christine Börner, Andrea Bedini, Volker Höllt and Jürgen Kraus
Molecular Pharmacology March 1, 2008, 73 (3) 1013-1019; DOI: https://doi.org/10.1124/mol.107.042945

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Research ArticleArticle

Analysis of Promoter Regions Regulating Basal and Interleukin-4-Inducible Expression of the Human CB1 Receptor Gene in T Lymphocytes

Christine Börner, Andrea Bedini, Volker Höllt and Jürgen Kraus
Molecular Pharmacology March 1, 2008, 73 (3) 1013-1019; DOI: https://doi.org/10.1124/mol.107.042945
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