Marijuana-derived Δ-9-tetrahydrocannabinol suppresses Th1/Th17 cell-mediated delayed-type hypersensitivity through microRNA regulation
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∆9-Tetrahydrocannabinol (THC) is one of the major bioactive cannabinoids derived from the Cannabis sativa plant and is known for its anti-inflammatory properties. Delayed-type hypersensitivity (DTH) is driven by proinflammatory T helper cells including the classic inflammatory Th1 lineage as well as the more recently discovered Th17 lineage. In the current study, we investigated whether THC can alter the induction of Th1/Th17 cells involved in mBSA-induced DTH response. THC treatment (20 mg/kg) of C57BL/6 mice with DTH caused decreased swelling and infiltration of immune cells at the site of antigen rechallenge. Additionally, THC treatment decreased lymphocyte activation as well as Th1/Th17 lineage commitment, including reduced lineage-specific transcription factors and cytokines. Interestingly, while DTH caused an overexpression of miR-21, which increases Th17 differentiation via SMAD7 inhibition, and downregulation of miR-29b, an IFN-γ inhibitor, THC treatment reversed this microRNA (miR) dysregulation. Furthermore, when we transfected primary cells from DTH mice with miR-21 inhibitor or miR-29b mimic, as seen with THC treatment, the expression of target gene message was directly impacted increasing SMAD7 and decreasing IFN-γ expression, respectively. In summary, the current study suggests that THC treatment during DTH response can simultaneously inhibit Th1/Th17 activation via regulation of microRNA (miRNA) expression.
• THC treatment inhibits simultaneous Th1/Th17 driven inflammation.
• THC treatment corrects DTH-mediated microRNA dysregulation.
• THC treatment regulates proinflammatory cytokines and transcription factors.
KeywordsHypersensitivity microRNA Cannabinoid THC Inflammation Th1/Th17 regulation
We wish to acknowledge the University of South Carolina School of Medicine Instrumentation Resource Facility (IRF) for their assistance with histology processing. This work was supported in part by the National Institute of Health Grants R01 MH094755, P01 AT003961 and P20 GM103641 to PN, R01 ES019313 to PN and MN, and R01 AT006888 and the Veterans Administration Merit Award BX001357 to MN.
Compliance with ethical standards
All experiments were conducted under an approved Institutional Animal Care and Use Committee animal protocol. This model of footpad induced DTH is well established and approved by IACUC (protocol# 2214-100895-090814: Mouse Models of Innate Immunity 1031 of the series Methods in Molecular Biology 101-107). The manuscript does not contain clinical studies or patient data.
Conflict of interest
The authors declare that they have no competing interests.
- 19.Newton CA, Chou PJ, Perkins I, Klein TW (2009) CB(1) and CB(2) cannabinoid receptors mediate different aspects of delta-9-tetrahydrocannabinol (THC)-induced T helper cell shift following immune activation by Legionella pneumophila infection. J Neuroimmune Pharmacol : Off J Soc NeuroImmune Pharmacol 4(1):92–102CrossRefGoogle Scholar
- 21.Rao R, Nagarkatti PS, Nagarkatti M (2014) Delta tetrahydrocannabinol attenuates Staphylococcal enterotoxin B-induced inflammatory lung injury and prevents mortality in mice by modulation of miR-17-92 cluster and induction of T-regulatory cells. Br J Pharmacol. doi: 10.1111/bph.13026 PubMedPubMedCentralGoogle Scholar
- 28.Hegde VL, Tomar S, Jackson A, Rao R, Yang X, Singh UP, Singh NP, Nagarkatti PS, Nagarkatti M (2013) Distinct microRNA expression profile and targeted biological pathways in functional myeloid-derived suppressor cells induced by Delta9-tetrahydrocannabinol in vivo: regulation of CCAAT/enhancer-binding protein alpha by microRNA-690. J Biol Chem 288(52):36810–36826CrossRefPubMedPubMedCentralGoogle Scholar
- 30.Correa F, Hernangomez-Herrero M, Mestre L, Loria F, Docagne F, Guaza C (2011) The endocannabinoid anandamide downregulates IL-23 and IL-12 subunits in a viral model of multiple sclerosis: evidence for a cross-talk between IL-12p70/IL-23 axis and IL-10 in microglial cells. Brain Behav Immun 25(4):736–749CrossRefPubMedGoogle Scholar
- 31.Lee HY, Stieger M, Yawalkar N, Kakeda M (2013) Cytokines and chemokines in irritant contact dermatitis. Mediat Inflamm 2013:916497Google Scholar
- 36.Manning AM, Bell FP, Rosenbloom CL, Chosay JG, Simmons CA, Northrup JL, Shebuski RJ, Dunn CJ, Anderson DC (1995) NF-kappa B is activated during acute inflammation in vivo in association with elevated endothelial cell adhesion molecule gene expression and leukocyte recruitment. J Inflamm 45(4):283–296PubMedGoogle Scholar
- 40.Busbee PB, Nagarkatti M, Nagarkatti PS (2015) Natural indoles, Indole-3-Carbinol (I3C) and 3,3′-Diindolylmethane (DIM), attenuate staphylococcal enterotoxin B-mediated liver injury by downregulating miR-31 expression and promoting caspase-2-mediated apoptosis. PLoS One 10(2):e0118506CrossRefPubMedPubMedCentralGoogle Scholar
- 42.Meza-Sanchez D, Perez-Montesinos G, Sanchez-Garcia J, Moreno J, Bonifaz LC (2011) Intradermal immunization in the ear with cholera toxin and its non-toxic beta subunit promotes efficient Th1 and Th17 differentiation dependent on migrating DCs. Eur J Immunol 41(10):2894–2904CrossRefPubMedGoogle Scholar
- 49.Smith KM, Guerau-de-Arellano M, Costinean S, Williams JL, Bottoni A, Mavrikis Cox G, Satoskar AR, Croce CM, Racke MK, Lovett-Racke AE et al (2012) miR-29ab1 deficiency identifies a negative feedback loop controlling Th1 bias that is dysregulated in multiple sclerosis. J Immunol 189(4):1567–1576CrossRefPubMedPubMedCentralGoogle Scholar
- 52.Chandra LC, Kumar V, Torben W, Vande Stouwe C, Winsauer P, Amedee A, Molina PE, Mohan M (2015) Chronic administration of delta9-tetrahydrocannabinol induces intestinal anti-inflammatory microRNA expression during acute simian immunodeficiency virus infection of rhesus macaques. J Virol 89(2):1168–1181CrossRefPubMedGoogle Scholar