IL-2 Suppression by Endocannabinoid Activation of PPARgamma

Summary

Principal Investigator: NORBERT EDWARD KAMINSKI
Abstract: The overall goal of this 5 year research plan is to elucidate the molecular mechanism responsible for the modulation of T cell function and interleukin-2 (IL-2) deregulation by the structurally-related endocannabinoids, anandamide (AEA) and 2-arachidonyl glycerol (2-AG). Presently, the teleological role of the endocannabinoid system is unknown but there is a growing body of evidence suggesting that it may significantly contribute to the maintenance of immunologic homeostasis. Numerous studies have demonstrated profound effects on biological systems by AEA and 2-AG, with the immune system representing one of the most extensively characterized. The significance of the current proposed studies is that they will provide direct mechanistic insight into the molecular mechanism by which endocannabinoids modulate T cell function, specifically IL-2 regulation. Novel preliminary results are presented demonstrating that IL-2 suppression by both AEA and 2-AG are dependent on COX-2 metabolism leading to the activation of the nuclear receptor, peroxisome proliferator activated receptor gamma (PPARgamma), independently of CB1 and CB2. Additional results are present suggesting that the specific mechanism involves the disruption of the nuclear factor of activated T cells (NFAT) by PPARgamma activation. Based on the observations described above and other preliminary data presented in the proposal, our present investigation will test the hypothesis: Suppression of IL-2 by the endocannabinoids, AEA and 2-AG, is mediated through disruption of NFAT regulation by two distinct cannabinoid receptor-independent mechanisms: (a) altered intracellular calcium regulation;and (b) activation of PPARgamma following COX-2-mediated conversion of AEA and 2-AG into PPARgamma agonists. We will test our hypothesis using the following specific aims (SA): SA1 is to characterize the role altered intracellular calcium regulation by AEA and 2-AG plays in deregulation of NFAT and, consequently, suppression of IL-2 gene expression;SA2 is to characterize the role of COX-2 on the deregulation of NFAT and suppression of IL-2 by AEA and 2-AG;SA3 is to characterize the role of PPARgamma activation by AEA and 2-AG treatment in altered NFAT regulation and suppression of IL-2;and SA4 is to identify and characterize the bioactive forms of AEA and 2-AG responsible for PPARgamma activation and to elucidate its contribution to IL- 2 suppression.
Funding Period: ----------------2005 - ---------------2011-
more information: NIH RePORT

Top Publications

  1. ncbi Cannabinoid-mediated elevation of intracellular calcium: a structure-activity relationship
    Gautham K Rao
    Department of Pharmacology and Toxicology, Center for Integrative Toxicology, 315 Food Safety Building, Michigan State University, East Lansing, MI 48824 1317, USA
    J Pharmacol Exp Ther 317:820-9. 2006
  2. pmc Δ9-tetrahydrocannabinol impairs the inflammatory response to influenza infection: role of antigen-presenting cells and the cannabinoid receptors 1 and 2
    Peer W F Karmaus
    Cell and Molecular Biology Program, Michigan State University, East Lansing, Michigan 48824, USA
    Toxicol Sci 131:419-33. 2013
  3. pmc Magnitude of stimulation dictates the cannabinoid-mediated differential T cell response to HIVgp120
    Weimin Chen
    Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, MI 48824, USA
    J Leukoc Biol 92:1093-102. 2012
  4. pmc 15-Deoxy-Δ¹²,¹⁴-prostaglandin J₂-glycerol, a putative metabolite of 2-arachidonyl glycerol and a peroxisome proliferator-activated receptor γ ligand, modulates nuclear factor of activated T cells
    Priyadarshini Raman
    Department of Pharmacology and Toxicology and the Center for Integrative Toxicology, Michigan State University, East Lansing, Michigan, USA
    J Pharmacol Exp Ther 342:816-26. 2012
  5. pmc Incensole acetate, an incense component, elicits psychoactivity by activating TRPV3 channels in the brain
    Arieh Moussaieff
    Department of Medicinal Chemistry and Natural Products, Medical Faculty, Hebrew University of Jerusalem, 91120, Jerusalem, Israel
    FASEB J 22:3024-34. 2008
  6. pmc Prostaglandin E2 glycerol ester, an endogenous COX-2 metabolite of 2-arachidonoylglycerol, induces hyperalgesia and modulates NFkappaB activity
    S Shu Jung Hu
    Department of Psychological and Brain Sciences, The Gill Center for Biomolecular Science, Indiana University, Bloomington, IN, USA
    Br J Pharmacol 153:1538-49. 2008
  7. pmc Compartmentalization of endocannabinoids into lipid rafts in a dorsal root ganglion cell line
    N Rimmerman
    Department of Psychological and Brain Sciences and the Gill Center for Biomolecular Sciences, Indiana University, Bloomington, IN 47405, USA
    Br J Pharmacol 153:380-9. 2008
  8. ncbi Fatty acyl amides of endogenous tetrahydroisoquinolines are active at the recombinant human TRPV1 receptor
    Neta Rimmerman
    The Gill Center for Biomolecular Science, 1101 East Tenth Street, Bloomington, IN 47405, USA
    Bioorg Med Chem 15:6164-9. 2007
  9. pmc Targeted lipidomics: discovery of new fatty acyl amides
    Bo Tan
    Gill Center for Biomolecular Science, Indiana University, Bloomington, IN, USA
    AAPS J 8:E461-5. 2006
  10. ncbi Improvement in middle cerebral artery structure and endothelial function in stroke-prone spontaneously hypertensive rats after macrophage depletion
    Paulo W Pires
    Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan, USA
    Microcirculation 20:650-61. 2013

Detail Information

Publications11

  1. ncbi Cannabinoid-mediated elevation of intracellular calcium: a structure-activity relationship
    Gautham K Rao
    Department of Pharmacology and Toxicology, Center for Integrative Toxicology, 315 Food Safety Building, Michigan State University, East Lansing, MI 48824 1317, USA
    J Pharmacol Exp Ther 317:820-9. 2006
    ....
  2. pmc Δ9-tetrahydrocannabinol impairs the inflammatory response to influenza infection: role of antigen-presenting cells and the cannabinoid receptors 1 and 2
    Peer W F Karmaus
    Cell and Molecular Biology Program, Michigan State University, East Lansing, Michigan 48824, USA
    Toxicol Sci 131:419-33. 2013
    ..Collectively, these studies suggest that Δ(9)-THC potently suppresses myeloid cell immune function, in a manner involving CB(1) and/or CB(2), thereby impairing immune responses to influenza infection...
  3. pmc Magnitude of stimulation dictates the cannabinoid-mediated differential T cell response to HIVgp120
    Weimin Chen
    Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, MI 48824, USA
    J Leukoc Biol 92:1093-102. 2012
    ..Overall, these data demonstrate differential modulation by cannabinoids of a HIV antigen-specific response and identify a possible mechanism responsible for this effect...
  4. pmc 15-Deoxy-Δ¹²,¹⁴-prostaglandin J₂-glycerol, a putative metabolite of 2-arachidonyl glycerol and a peroxisome proliferator-activated receptor γ ligand, modulates nuclear factor of activated T cells
    Priyadarshini Raman
    Department of Pharmacology and Toxicology and the Center for Integrative Toxicology, Michigan State University, East Lansing, Michigan, USA
    J Pharmacol Exp Ther 342:816-26. 2012
    ..Collectively, our findings suggest that 15d-PGJ₂-G increases active nuclear HDM2, which could lead to a decrease in NFAT2 and IL-2 suppression...
  5. pmc Incensole acetate, an incense component, elicits psychoactivity by activating TRPV3 channels in the brain
    Arieh Moussaieff
    Department of Medicinal Chemistry and Natural Products, Medical Faculty, Hebrew University of Jerusalem, 91120, Jerusalem, Israel
    FASEB J 22:3024-34. 2008
    ..Furthermore, the biochemical and pharmacological effects of IA may provide a biological basis for deeply rooted cultural and religious traditions...
  6. pmc Prostaglandin E2 glycerol ester, an endogenous COX-2 metabolite of 2-arachidonoylglycerol, induces hyperalgesia and modulates NFkappaB activity
    S Shu Jung Hu
    Department of Psychological and Brain Sciences, The Gill Center for Biomolecular Science, Indiana University, Bloomington, IN, USA
    Br J Pharmacol 153:1538-49. 2008
    ..We examined whether prostaglandin E2 glycerol ester (PGE2-G), a COX-2 metabolite of 2-AG, occurs endogenously and affects nociception and immune responses...
  7. pmc Compartmentalization of endocannabinoids into lipid rafts in a dorsal root ganglion cell line
    N Rimmerman
    Department of Psychological and Brain Sciences and the Gill Center for Biomolecular Sciences, Indiana University, Bloomington, IN 47405, USA
    Br J Pharmacol 153:380-9. 2008
    ..To investigate the compartmentalization of the machinery for AEA and 2-AG signalling, we studied their partitioning into lipid raft fractions isolated from a dorsal root ganglion X neuroblastoma cell line (F-11)...
  8. ncbi Fatty acyl amides of endogenous tetrahydroisoquinolines are active at the recombinant human TRPV1 receptor
    Neta Rimmerman
    The Gill Center for Biomolecular Science, 1101 East Tenth Street, Bloomington, IN 47405, USA
    Bioorg Med Chem 15:6164-9. 2007
    ..Three compounds showed partial TRPV1 agonism with EC(50) values in the low micromolar range and maximal efficacies between 25% and 55% of capsaicin...
  9. pmc Targeted lipidomics: discovery of new fatty acyl amides
    Bo Tan
    Gill Center for Biomolecular Science, Indiana University, Bloomington, IN, USA
    AAPS J 8:E461-5. 2006
    ....
  10. ncbi Improvement in middle cerebral artery structure and endothelial function in stroke-prone spontaneously hypertensive rats after macrophage depletion
    Paulo W Pires
    Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan, USA
    Microcirculation 20:650-61. 2013
    ..Macrophages might be involved in remodeling of the cerebral vasculature. We hypothesized that peripheral macrophage depletion would improve MCA structure and function in hypertensive rats...
  11. pmc Deletion of cannabinoid receptors 1 and 2 exacerbates APC function to increase inflammation and cellular immunity during influenza infection
    Peer W F Karmaus
    Cell and Molecular Biology Program, Center for Integrative Toxicology, Michigan State University, East Lansing, MI 48824, USA
    J Leukoc Biol 90:983-95. 2011
    ..Collectively, these findings implicate a role for CB(1) and CB(2) on APCs in regulating immune responses and immune homeostasis...