Previous results from our laboratory indicate that immune suppression by cannabinoids is mediated through cannabinoid receptors expressed on immunocompetent cells, most notably T-cells which we have found to exhibits a marked sensitivity. This is indicated by an inhibition of T-cell mediated responses and Il-2 expression in the presence of cannabinoids. We have also shown that ligand binding to cannabinoid receptors inhibits cAMP signal transduction in T-cells as evidenced by decreased; (i) cAMP formation; (ii) protein kinase A activity; and (iii) binding by CREB/ATF transcription factors to their cognate DNA binding site, cAMP responsive element (CRE). CREB/ATF regulatory proteins also dimerize with Fos and Jun family members to help regulate gene transcription at AP-1 sites (e.g., IL- 2). Our studies suggest that the inhibition of cAMP signaling is responsible for immune inhibition by cannabinoids based on three critical observations: 91) membrane permeable cAMP analogs reversed the immunoinhibitory effects produced by cannabinoids; (ii) pertussis toxin pretreatment of splenocytes abrogated cannbinoid-induced immune suppression and inhibition of adenylate cyclase; and (iii) glucagon, which stimulates adenylate cyclase activity through interaction with its own G-protein coupled receptor, reversed the inhibitory effects produced by cannabinoids. Based on the observations described above our present investigation will have two objectives; (1) to identify which specific cAMP-regulated transcription factors are inhibited by cannabinoids during T-cell activation; and (2) to identify specific cAMP regulated genes that exhibit altered expression during T-cell activation in athe presence of cannabinoids. In SA#1, we will identify the DNA binding proteins within the CREB/ATF family of transcription regulators that are involved in T-cell activation and which concomitantly exhibit decreased DNA binding in the presence of cannabinoids. In SA#2, we will characterize the specific time course and magnitude of transcriptional dysregulation at CRE and AP-1 DNA regulatory sites by cannabinoids following T-cell activation using CRE and AP-1 luciferase reporter constructs. In SA#3, we will characterize cannabinoid-mediated inhibition of IL-2 gene expression using I-2 luciferase reporter constructs. In SA#4, we will identify cAMP-regulated genes involved in T-cell activation whose expression is altered by cannabinoid-treatment. Lastly, in SA#5 we will, characterize genes involved in T-cell activation that exhibit sensitivity to dysregulation by cannabinoids.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA007908-08
Application #
2683828
Study Section
Special Emphasis Panel (SRCD (08))
Program Officer
Sharp, Charles
Project Start
1992-04-01
Project End
2001-03-31
Budget Start
1998-04-15
Budget End
1999-03-31
Support Year
8
Fiscal Year
1998
Total Cost
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
Henriquez, Joseph E; Rizzo, Michael D; Crawford, Robert B et al. (2018) Interferon-?-Mediated Activation of T Cells from Healthy and HIV-Infected Individuals Is Suppressed by ?9-Tetrahydrocannabinol. J Pharmacol Exp Ther 367:49-58
Rizzo, Michael D; Crawford, Robert B; Henriquez, Joseph E et al. (2018) HIV-infected cannabis users have lower circulating CD16+ monocytes and IFN-?-inducible protein 10 levels compared with nonusing HIV patients. AIDS 32:419-429
Henriquez, Joseph; Zhou, Jiajun; Li, Jinpeng et al. (2017) Application of gene specific mRNA level determinations in individual cells using flow cytometry-based PrimeFlow™ in immunotoxicology. Toxicol Appl Pharmacol 337:39-44
Henriquez, Joseph E; Rizzo, Michael D; Schulz, Matthias A et al. (2017) ?9-Tetrahydrocannabinol Suppresses Secretion of IFN? by Plasmacytoid Dendritic Cells From Healthy and HIV-Infected Individuals. J Acquir Immune Defic Syndr 75:588-596
Chen, Weimin; Crawford, Robert B; Kaplan, Barbara L F et al. (2015) Modulation of HIVGP120 Antigen-Specific Immune Responses In Vivo by ?9-Tetrahydrocannabinol. J Neuroimmune Pharmacol 10:344-55
Chen, Weimin; Zhang, Quanxuan; Kaplan, Barbara L F et al. (2014) Induced T cell cytokine production is enhanced by engineered nanoparticles. Nanotoxicology 8 Suppl 1:11-23
Karmaus, Peer W F; Wagner, James G; Harkema, Jack R et al. (2013) Cannabidiol (CBD) enhances lipopolysaccharide (LPS)-induced pulmonary inflammation in C57BL/6 mice. J Immunotoxicol 10:321-8
Pires, Paulo W; Girgla, Saavia S; McClain, Jonathon L et al. (2013) Improvement in middle cerebral artery structure and endothelial function in stroke-prone spontaneously hypertensive rats after macrophage depletion. Microcirculation 20:650-61
Karmaus, Peer W F; Chen, Weimin; Crawford, Robert et al. (2013) ?9-tetrahydrocannabinol impairs the inflammatory response to influenza infection: role of antigen-presenting cells and the cannabinoid receptors 1 and 2. Toxicol Sci 131:419-33
Ngaotepprutaram, Thitirat; Kaplan, Barbara L F; Kaminski, Norbert E (2013) Impaired NFAT and NF?B activation are involved in suppression of CD40 ligand expression by ?(9)-tetrahydrocannabinol in human CD4(+) T cells. Toxicol Appl Pharmacol 273:209-18

Showing the most recent 10 out of 54 publications