Marijuana-derived Δ-9-tetrahydrocannabinol suppresses Th1/Th17 cell-mediated delayed-type hypersensitivity through microRNA regulation

J Mol Med (Berl). 2016 Sep;94(9):1039-51. doi: 10.1007/s00109-016-1404-5. Epub 2016 Apr 1.

Abstract

∆(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.

Key messages: • THC treatment inhibits simultaneous Th1/Th17 driven inflammation. • THC treatment corrects DTH-mediated microRNA dysregulation. • THC treatment regulates proinflammatory cytokines and transcription factors.

Keywords: Cannabinoid; Hypersensitivity; Inflammation; THC; Th1/Th17 regulation; microRNA.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Cytokines / metabolism
  • Disease Models, Animal
  • Dronabinol / pharmacology*
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation / drug effects
  • Hypersensitivity, Delayed / drug therapy
  • Hypersensitivity, Delayed / genetics*
  • Hypersensitivity, Delayed / immunology*
  • Hypersensitivity, Delayed / pathology
  • Inflammation Mediators / metabolism
  • Lymphocyte Activation / drug effects
  • Lymphocyte Activation / immunology
  • Mice
  • MicroRNAs / genetics*
  • RNA Interference
  • Th1 Cells / drug effects*
  • Th1 Cells / physiology*
  • Th17 Cells / drug effects*
  • Th17 Cells / physiology*
  • Transcription Factors / genetics

Substances

  • Cytokines
  • Inflammation Mediators
  • MicroRNAs
  • Transcription Factors
  • Dronabinol