β-Caryophyllene Reduces the Inflammatory Phenotype of Periodontal Cells by Targeting CB2 Receptors.

Giacomo Picciolo,Mario Vaccaro,Giovanni Pallio,Domenica Altavilla,Francesco Squadrito,Natasha Irrera,Giacomo Oteri

doi:10.3390/biomedicines8060164

Abstract

Human gingival fibroblasts (GF) and human oral mucosa epithelial cells (EC) with an inflammatory phenotype represent a valuable experimental paradigm to explore the curative activity of agents to be used in oral mucositis. The role of cannabinoid receptor 2 (CB2) has not yet been investigated in oral mucositis. The aim of this study was to evaluate the therapeutic potential of β-Caryophyllene (BCP), a CB2 agonist, in an in vitro model of oral mucositis. GF and EC were stimulated with LPS (2 µg/mL) alone or in combination with BCP; a group of LPS challenged GF and EC were treated with BCP and AM630, a CB2 antagonist. LPS increased the inflammatory cytokines TNF-α, IL-1β, IL-6 and IL-17A whereas it decreased the anti-inflammatory cytokine IL-13. The upstream signals were identified in an augmented expression of NF-κB and STAT-3 and in reduced mRNA levels of PPARγ and PGC-1α. BCP blunted the LPS-induced inflammatory phenotype and this effect was reverted by the CB2 antagonist AM630. These results suggest that CB2 receptors are an interesting target to develop innovative strategies for oral mucositis and point out that BCP exerts a marked curative effect in a preclinical model of oral mucositis which deserves to be confirmed in a clinical setting.

Highlights

Oral mucositis (OM) is a clinical condition characterized by a marked inflammatory reaction that results in erythematous lesions, ulcers, dysphagia and inability to afford and ensure a physiological calories intake that leads to interrupting life-saving treatments in cancer patients [1,2,3,4]
LPS challenge resulted in a marked expression of TNF-α and IL-1β with a concomitant reduced mRNA of IL-13 in both gingival fibroblasts and oral mucosa epithelial cells (p < 0.0001 vs. CTRL; Figure 1)
“in vitro” an inflammatory experimentalphenotype paradigm characterized to mimic oral components the cell types acquired mucositis. This aim we primed with humanan gingival fibroblasts and oral mucosa epithelial

Summary

Introduction

Oral mucositis (OM) is a clinical condition characterized by a marked inflammatory reaction that results in erythematous lesions, ulcers, dysphagia and inability to afford and ensure a physiological calories intake that leads to interrupting life-saving treatments in cancer patients [1,2,3,4]. Oral mucositis may complicate and/or be a clinical manifestation of peri-implantitis a common complication of dental implants, showing a prevalence of at least 20% in patients that have undergone this surgical procedure [5,6,7,8]. Biomedicines 2020, 8, 164 stimuli and progressive bone loss as in peri-implantitis [9,10], a common pathway converges in an exaggerated production of reactive oxygen species (ROS) released by both epithelial cells and gingival fibroblasts [11]. ROS boosts the translocation to the nucleus of Nuclear Factor Kappa

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