Previous studies in this laboratory have demonstrated a marked and concentration-dependent inhibition of IL-2 by a putative endogenous cannabinoid, 2-arachidonyl glycerol (2-AG), in activated T cells, but it is yet unknown whether this inhibition is mediated through the cannabinoid receptors, CB1 and/or CB2. The CB2 receptor is of particular interest because it has a much higher level of expression than the CB1 receptor. The majority of our observations have thus far been in murine T cells. We are now interested in characterizing the effect of 2-AG in two human T cell lines, Jurkat E6-1 and HPB-ALL, which express an aberrant and normal CB2 receptor, respectively. The Jurkat and HPB-ALL cell lines in conjunction with the CB2 antagonist, SR144528, will allow us to determine if the activity of 2-AG in human T cells is mediated through the CB2 receptor. Preliminary studies led to the following observations: a) the inhibition of IL2 by 2-AG was not reversed by CB1/CB2 antagonists; b) 2-AG inhibited IL-2 transcription in HPB-ALL cells, but not in Jurkat cells, which express an aberrant CB2 receptor; and c) paradoxically, 2-AG also enhances T cell proliferation. These observations led to the hypothesis: 2-arachidonyl glycerol enhances T cell proliferation in a CB1/CB2 independent mechanism through alterations in cell cycle control and/or ERK MAP kinases, while inhibiting IL-2 production. This hypothesis will be tested using three specific aims (SA): SA1) characterization of the effects of 2-AG upon IL-2 transcription and secretion in human T cells; SA2) characterization on the effects of 2-AG upon T cell proliferation in human T cells; and SA3) characterization of the effects of 2-AG on the cyclin dependent kinase inhibitors, p16, p21, and p27, and the mitogen-activated kinases, ERK1 and ERK2.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
1F31DA015276-01
Application #
6487951
Study Section
Human Development Research Subcommittee (NIDA)
Program Officer
Babecki, Beth
Project Start
2002-03-16
Project End
Budget Start
2002-03-16
Budget End
2003-03-15
Support Year
1
Fiscal Year
2002
Total Cost
$24,443
Indirect Cost
Name
Michigan State University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
193247145
City
East Lansing
State
MI
Country
United States
Zip Code
48824