Cannabinol enhancement of interleukin-2 (IL-2) expression by T cells is associated with an increase in IL-2 distal nuclear factor of activated T cell activity

Mol Pharmacol. 2002 Feb;61(2):446-54. doi: 10.1124/mol.61.2.446.


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 kappa 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, Delta(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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Motifs
  • Animals
  • Calcium-Calmodulin-Dependent Protein Kinases / physiology
  • Camphanes / pharmacology
  • Cannabinol / pharmacology*
  • Cyclohexanols / pharmacology
  • DNA / drug effects
  • DNA / metabolism
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Dose-Response Relationship, Drug
  • Dronabinol / pharmacology
  • In Vitro Techniques
  • Interleukin-2 / biosynthesis*
  • Interleukin-2 / genetics
  • Interleukin-2 / metabolism
  • Lymphocyte Activation / drug effects
  • Mice
  • Mice, Inbred C57BL
  • NF-kappa B / metabolism
  • NFATC Transcription Factors
  • Nuclear Proteins*
  • Pyrazoles / pharmacology
  • RNA, Messenger / drug effects
  • RNA, Messenger / metabolism
  • Receptors, Cannabinoid
  • Receptors, Drug / antagonists & inhibitors
  • T-Lymphocytes / drug effects*
  • T-Lymphocytes / metabolism
  • Transcription Factor AP-1 / metabolism
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Transcription, Genetic / drug effects
  • Transfection


  • Camphanes
  • Cyclohexanols
  • DNA-Binding Proteins
  • Interleukin-2
  • NF-kappa B
  • NFATC Transcription Factors
  • Nuclear Proteins
  • Pyrazoles
  • RNA, Messenger
  • Receptors, Cannabinoid
  • Receptors, Drug
  • SR 144528
  • Transcription Factor AP-1
  • Transcription Factors
  • Dronabinol
  • Cannabinol
  • 3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol
  • DNA
  • Calcium-Calmodulin-Dependent Protein Kinases