Rare Phytocannabinoids Exert Anti-Inflammatory Effects on Human Keratinocytes via the Endocannabinoid System and MAPK Signaling Pathway
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Published:2023-02-01
Issue:3
Volume:24
Page:2721
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ISSN:1422-0067
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Container-title:International Journal of Molecular Sciences
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language:en
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Short-container-title:IJMS
Author:
Tortolani Daniel12ORCID, Di Meo Camilla3ORCID, Standoli Sara3ORCID, Ciaramellano Francesca1ORCID, Kadhim Salam4, Hsu Eric4, Rapino Cinzia1ORCID, Maccarrone Mauro25ORCID
Affiliation:
1. Department of Veterinary Medicine, University of Teramo, 64100 Teramo, Italy 2. European Center for Brain Research (CERC), Santa Lucia Foundation IRCCS, 00143 Rome, Italy 3. Department of Bioscience and Technology for Food Agriculture and Environment, University of Teramo, 64100 Teramo, Italy 4. InMed Pharmaceuticals Inc., Vancouver, BC V6C 1B4, Canada 5. Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila, 67100 L’Aquila, Italy
Abstract
Increasing evidence supports the therapeutic potential of rare cannabis-derived phytocannabinoids (pCBs) in skin disorders such as atopic dermatitis, psoriasis, pruritus, and acne. However, the molecular mechanisms of the biological action of these pCBs remain poorly investigated. In this study, an experimental model of inflamed human keratinocytes (HaCaT cells) was set up by using lipopolysaccharide (LPS) in order to investigate the anti-inflammatory effects of the rare pCBs cannabigerol (CBG), cannabichromene (CBC), Δ9-tetrahydrocannabivarin (THCV) and cannabigerolic acid (CBGA). To this aim, pro-inflammatory interleukins (IL)-1β, IL-8, IL-12, IL-31, tumor necrosis factor (TNF-β) and anti-inflammatory IL-10 levels were measured through ELISA quantification. In addition, IL-12 and IL-31 levels were measured after treatment of HaCaT cells with THCV and CBGA in the presence of selected modulators of endocannabinoid (eCB) signaling. In the latter cells, the activation of 17 distinct proteins along the mitogen-activated protein kinase (MAPK) pathway was also investigated via Human Phosphorylation Array. Our results demonstrate that rare pCBs significantly blocked inflammation by reducing the release of all pro-inflammatory ILs tested, except for TNF-β. Moreover, the reduction of IL-31 expression by THCV and CBGA was significantly reverted by blocking the eCB-binding TRPV1 receptor and by inhibiting the eCB-hydrolase MAGL. Remarkably, THCV and CBGA modulated the expression of the phosphorylated forms (and hence of the activity) of the MAPK-related proteins GSK3β, MEK1, MKK6 and CREB also by engaging eCB hydrolases MAGL and FAAH. Taken together, the ability of rare pCBs to exert an anti-inflammatory effect in human keratinocytes through modifications of eCB and MAPK signaling opens new perspectives for the treatment of inflammation-related skin pathologies.
Funder
InMed Pharmaceuticals Inc.
Subject
Inorganic Chemistry,Organic Chemistry,Physical and Theoretical Chemistry,Computer Science Applications,Spectroscopy,Molecular Biology,General Medicine,Catalysis
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