CB2 receptor activation causes an ERK1/2-dependent inflammatory response in human RPE cells

Abstract

A chronic low-level inflammation contributes to the pathogenesis of age-related macular degeneration (AMD), the most common cause of blindness in the elderly in Western countries. The loss of central vision results from attenuated maintenance of photoreceptors due to the degeneration of retinal pigment epithelium (RPE) cells beneath the photoreceptor layer. It has been proposed that pathologic inflammation initiated in RPE cells could be regulated by the activation of type 2 cannabinoid receptors (CB2). Here, we have analysed the effect of CB2 activation on cellular survival and inflammation in human RPE cells. RPE cells were treated with the selective CB2 agonist JWH-133 in the presence or absence of the oxidative stressor 4-hydroxynonenal. Thereafter, cellular viability as well as the release of pro-inflammatory cytokines and potential underlying signalling pathways were analysed. Our results show that JWH-133 led to increased intracellular Ca2+ levels, suggesting that RPE cells are capable of responding to a CB2 agonist. JWH-133 could not prevent oxidative stress-induced cell death. Instead, 10 µM JWH-133 increased cell death and the release of proinflammatory cytokines in an ERK1/2-dependent manner. In contrast to previous findings, CB2 activation increased, rather than reduced inflammation in RPE cells.

Pharmacological Properties, Therapeutic Potential and Molecular Mechanisms of JWH133, a CB2 Receptor-Selective Agonist

“…Thus, CB2R activation by JWH133 mitigated inflammatory reaction and swelling, indicating that CB2R agonists might be a beneficial target for treating inflammatory pain responses. In contrast, JWH133 increased intracellular Ca 2+ levels in human retinal pigment epithelial cells, indicating their responsiveness to JWH133 (Hytti et al, 2017). However, JWH133 did not inhibit oxidative stress-induced apoptosis mediated by reactive aldehyde 4-hydroxynonenal.…”

Cannabinoid type‐2 receptor agonist, inverse agonist, and anandamide regulation of inflammatory responses in IL‐1β stimulated primary human periodontal ligament fibroblasts

“…It has been reported that cannabinoids positively regulate gingival fibroblasts by activation of p‐ERK, p‐p38, and Akt, 118 while cell‐specific differences are also seen in such as p‐ERK and Akt are activated in monocytes, 119 but not p‐p38. CB2R agonists inhibit cAMP production which has been demonstrated to result in phosphorylation of ERK in the in vitro models 109,111,120‐123 . On the contrary, inverse agonists increase cAMP levels that could activate protein kinase A (PKA) and subsequent phosphorylation of ERK can occur as such is reported in dental pulpal cells 124 and pancreatic β cells 125,126 .…”

Identification and biochemical analyses of selective CB2 agonists

“…Studies of the cannabinoid CB 2 receptor agonists acting on cells that endogenously express the cannabinoid CB 2 receptor are largely consistent with our results. Cannabinoids 2-AG and JWH-133 induce phosphorylation of ERK1/2 in T lymphocytes through interactions with the cannabinoid CB 2 receptor (Coopman et al, 2007) and JWH-133 also causes cannabinoid CB 2 receptor-mediated ERK1/2 phosphorylation in retinal pigment epithelium (RPE) cells (Hytti et al, 2017). In microglia, endocannabinoid AEA also activates ERK1/2 as a result of binding to the cannabinoid CB 2 receptor (Correa et al, 2009a;Correa et al, 2009b).…”