Δ 9-Tetrahydrocannabinol reverses TNFα-induced increase in airway epithelial cell permeability through CB 2 receptors

Biochem Pharmacol. 2016 Nov 15;120:63-71. doi: 10.1016/j.bcp.2016.09.008. Epub 2016 Sep 15.

Abstract

Despite pharmacological treatment, bronchial hyperresponsiveness continues to deteriorate as airway remodelling persists in airway inflammation. Previous studies have demonstrated that the phytocannabinoid Δ9-tetrahydrocannabinol (THC) reverses bronchoconstriction with an anti-inflammatory action. The aim of this study was to investigate the effects of THC on bronchial epithelial cell permeability after exposure to the pro-inflammatory cytokine, TNFα. Calu-3 bronchial epithelial cells were cultured at air-liquid interface. Changes in epithelial permeability were measured using Transepithelial Electrical Resistance (TEER), then confirmed with a paracellular permeability assay and expression of tight junction proteins by Western blotting. Treatment with THC prevented the TNFα-induced decrease in TEER and increase in paracellular permeability. Cannabinoid CB1 and CB2 receptor-like immunoreactivity was found in Calu-3 cells. Subsequent experiments revealed that pharmacological blockade of CB2, but not CB1 receptor inhibited the THC effect. Selective stimulation of CB2 receptors displayed a similar effect to that of THC. TNFα decreased expression of the tight junction proteins occludin and ZO-1, which was prevented by pre-incubation with THC. These data indicate that THC prevents cytokine-induced increase in airway epithelial permeability through CB2 receptor activation. This highlights that THC, or other cannabinoid receptor ligands, could be beneficial in the prevention of inflammation-induced changes in airway epithelial cell permeability, an important feature of airways diseases.

Keywords: ACEA (PubChem CID: 5311006); AM251 (PubChem CID: 2125); Airway; Cannabinoid receptors; Epithelium; HU-210 (PubChem CID: 9821569); JWH133 (PubChem CID: 6918505); SR144528 (PubChem CID: 3081355); THC; Tight junctions; Δ(9)-tetrahydrocannabinol (PubChem CID: 16078).

MeSH terms

  • Algorithms
  • Anti-Inflammatory Agents, Non-Steroidal / metabolism
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
  • Bronchi / drug effects*
  • Bronchi / immunology
  • Bronchi / metabolism
  • Cannabinoid Receptor Agonists / metabolism
  • Cannabinoid Receptor Agonists / pharmacology*
  • Cannabinoid Receptor Antagonists / pharmacology
  • Cell Line, Tumor
  • Cell Membrane Permeability / drug effects
  • Dronabinol / metabolism
  • Dronabinol / pharmacology*
  • Electric Impedance
  • Hallucinogens / metabolism
  • Hallucinogens / pharmacology*
  • Humans
  • Interleukin-1beta / antagonists & inhibitors
  • Interleukin-1beta / metabolism
  • Kinetics
  • Ligands
  • Occludin / agonists
  • Occludin / antagonists & inhibitors
  • Occludin / metabolism
  • Permeability / drug effects
  • Receptor, Cannabinoid, CB2 / agonists*
  • Receptor, Cannabinoid, CB2 / antagonists & inhibitors
  • Receptor, Cannabinoid, CB2 / metabolism
  • Respiratory Mucosa / drug effects*
  • Respiratory Mucosa / immunology
  • Respiratory Mucosa / metabolism
  • Tight Junction Proteins / agonists
  • Tight Junction Proteins / antagonists & inhibitors
  • Tight Junction Proteins / metabolism
  • Tight Junctions / drug effects
  • Tight Junctions / metabolism
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors
  • Tumor Necrosis Factor-alpha / metabolism
  • Zonula Occludens-1 Protein / agonists
  • Zonula Occludens-1 Protein / antagonists & inhibitors
  • Zonula Occludens-1 Protein / metabolism

Substances

  • Anti-Inflammatory Agents, Non-Steroidal
  • CNR2 protein, human
  • Cannabinoid Receptor Agonists
  • Cannabinoid Receptor Antagonists
  • Hallucinogens
  • IL1B protein, human
  • Interleukin-1beta
  • Ligands
  • OCLN protein, human
  • Occludin
  • Receptor, Cannabinoid, CB2
  • TJP1 protein, human
  • TNF protein, human
  • Tight Junction Proteins
  • Tumor Necrosis Factor-alpha
  • Zonula Occludens-1 Protein
  • Dronabinol