title: Δ9-Tetrahydrocannabinol reverses TNFα-induced increase in airway epithelial cell permeability through CB2receptors.
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 CB1and CB2receptor-like immunoreactivity was found in Calu-3 cells. Subsequent experiments revealed that pharmacological blockade of CB2, but not CB1receptor inhibited the THC effect. Selective stimulation of CB2receptors 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 CB2receptor 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.
authors.affiliation: Cell Signalling and Pharmacology Research Group, School of Life Sciences, University of Nottingham, Medical School, Nottingham NG7 2UH, UK.
authors.forename: Valerie C M
authors.initials: VC
authors.lastname: Shang
authors.affiliation: Cell Signalling and Pharmacology Research Group, School of Life Sciences, University of Nottingham, Medical School, Nottingham NG7 2UH, UK.
authors.forename: David A
authors.initials: DA
authors.lastname: Kendall
authors.affiliation: Cell Signalling and Pharmacology Research Group, School of Life Sciences, University of Nottingham, Medical School, Nottingham NG7 2UH, UK. Electronic address: richard.roberts@nottingham.ac.uk.
authors.forename: Richard E
authors.initials: RE
authors.lastname: Roberts
mesh_terms: D000465:Algorithms; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000378:metabolism / Q000494:pharmacology*; D001980:Bronchi / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D063386:Cannabinoid Receptor Agonists / Q000378:metabolism / Q000494:pharmacology*; D063387:Cannabinoid Receptor Antagonists / Q000494:pharmacology; D045744:Cell Line, Tumor; D002463:Cell Membrane Permeability / Q000187:drug effects; D013759:Dronabinol / Q000378:metabolism / Q000494:pharmacology*; D017097:Electric Impedance; D006213:Hallucinogens / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D053583:Interleukin-1beta / Q000037:antagonists & inhibitors / Q000378:metabolism; D007700:Kinetics; D008024:Ligands; D062793:Occludin / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D010539:Permeability / Q000187:drug effects; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000378:metabolism; D020545:Respiratory Mucosa / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D062725:Tight Junction Proteins / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D019108:Tight Junctions / Q000187:drug effects / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism; D062826:Zonula Occludens-1 Protein / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; C588309:CNR2 protein, human; D063386:Cannabinoid Receptor Agonists; D063387:Cannabinoid Receptor Antagonists; D006213:Hallucinogens; C508585:IL1B protein, human; D053583:Interleukin-1beta; D008024:Ligands; C568985:OCLN protein, human; D062793:Occludin; D043885:Receptor, Cannabinoid, CB2; C569042:TJP1 protein, human; C439524:TNF protein, human; D062725:Tight Junction Proteins; D014409:Tumor Necrosis Factor-alpha; D062826:Zonula Occludens-1 Protein; D013759:Dronabinol
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)