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.
Highlights
Excessive inflammatory processes in human retinal pigment epithelial (RPE) cells are associated with the development of age-related macular degeneration (AMD)[1,2], the leading cause of visual impairment in the elderly in the Western world[3]
One previous report indicated that the activation of the cannabinoid receptor type 2 (CB2) receptor in ARPE-19 cells is protective against oxidative stress-related cell death caused by hydrogen peroxide[21]
After observing that JWH-133 increased the release of pro-inflammatory cytokines from retinal pigment epithelium (RPE) cells, we examined the phosphorylation status of ERK1/2, which has previously been associated with CB2 receptor activation[26,27] In our experiments, 10 μM JWH-133 increased the phosphorylation of ERK1/2 in ARPE-19 cells (Fig. 4a)
Summary
Excessive inflammatory processes in human retinal pigment epithelial (RPE) cells are associated with the development of age-related macular degeneration (AMD)[1,2], the leading cause of visual impairment in the elderly in the Western world[3]. The G-protein-coupled receptor is one of the two receptors targeted by pharmacologically active, plant-derived cannabinoids as well as the body’s own endocannabinoids[11,12]. The CB2 receptor is expressed predominantly in the periphery, especially on immune cells, and has been linked to many of the beneficial, anti-inflammatory effects of cannabinoids[13]. Specific agonists of CB2 have been developed to facilitate the studies of the receptor’s effects and to avoid side-effects associated with CB1 activation[15,16]. CB2 activation was found to reduce the hydrogen peroxide-induced death of ARPE-19 and primary human RPE cells, suggesting a beneficial effect of CB2 receptor activation in the treatment or the prevention of AMD21. Studies on the role of CB2 receptor in human RPE cells are scarce and data about its effects on inflammation in other cells are inconsistent
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