Previous results from this laboratory demonstrate that T cells are markedly sensitive to modulation by cannabinoids as evidenced by altered interleukin-2 (IL-2) gene expression. Our results suggest that the molecular mechanism for IL-2 modulation by cannabinoids is complex and involves multiple signaling cascades whose modulation is both cannabinoid receptor-dependent and -independent. The following key observations support this premise: (a) cannabinoid-treatment induced a marked, sustained and concentration dependent elevation in intracellular ([Ca+2]i) that was attenuated by cannabinoid receptor antagonists; (b) concordant with elevated [Ca+ cannabinoid treatment disrupted the activity of the downstream effectors, NF-AT, AP-1, ERK MAP kinases and calcium/calmodulin-dependent kinase, CaM KII; and (c) cannabinoid treatment induced rapid nuclear translocation and DNA binding of glucocorticoid receptors (GR). Based on these and other findings, the overall goal of this five year research plan is to test the Hypothesis: Cannabinoid-induced inhibition of T cell activation, as assessed by IL-2 gene expression, is mediated concomitantly through cannabinoid receptor-dependent and -independent mechanisms involving sustained intracellular calcium elevation and activation of glucocorticoid receptors, respectively. Our hypothesis will be test using four specific aims (SA). In SA#1, we will characterize cannabinoid-mediated [Ca+ elevation and the role of CB 1 and/or CB2; In SA#2 we will characterize the activation of CaM KII by cannabinoid- mediated enhancement in [Ca2]. In SA#3 we will characterize the downstream consequences of cannabinoid-mediated enhanced of [Ca2] and CaM KII activation on IL-2 regulation. Lastly, in SA#4 we will characterize the role of cannabinoid-mediated GR activation in T cell dysfunction. The significance of the results from these studies is that they will provide important new insights into the molecular mechanism(s) responsible for cannabinoid-mediated immune suppression.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA007908-13
Application #
6865479
Study Section
AIDS and Related Research 8 (AARR)
Program Officer
Sharp, Charles
Project Start
1992-04-01
Project End
2008-01-31
Budget Start
2005-02-01
Budget End
2006-01-31
Support Year
13
Fiscal Year
2005
Total Cost
$261,625
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

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