Multitargeting by STW5 in a rat model for gastroesophageal reflux disease and in HET1A-cells involves MAP-Kinase and G-protein coupled receptor signaling

We earlier showed that STW5, a herbal preparation composed of Iberis amara, Angelicae radix, Matricariae flos, Carvi fructus, Cardui mariae fructus, Melissae folium, Menthae piperitae folium, Chelidonii herba and Liquiritiae radix, and used in Irritable bowel syndrome, reduces proinflammatory signatures in murine models of Gastroesophageal reflux disease (GERD)[1]. Here we investigated which receptors and cell signaling pathways are involved including the lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) and the G-protein coupled receptor GPR84 which are activated during inflammation [2,3]. Rats received treatments with STW5 or the proton pump inhibitor Omeprazole (O) [1]. Whole cell lysates of esophagi were evaluated by Western Blot for GPR84, LOX-1 and MAPK p38. Human esophageal squamous HET-1A cells were further investigated. Here inflammation was induced with Capsaicin (50µM, 18h). Cells were treated with either STW5 (0.17; 0.5; 1.7; 5 µl/ml) or O (10 µg/ml; 30 µg/ml). MAPKs p38, ERK1 and 2 were determined. LOX-1 was detected in the esophagi of rats with esophagitis. GPR84 was increased in the esophagitis group compared to the sham group and down regulated by STW5 and O (p < 0.01). In the sham group neither total p38 MAPK nor the phosphorylation of p38 was increased. Treatment of STW5 inhibited the phosphorylation of p38 MAPK in the tissue (p < 0.01), but did not influence increases in the total amount of p38 of the esophagitis group. In HET1A capsaicin increased the expression of GPR84 which was reduced by the high concentration of STW5. Capsaicin induced an increase in the phosphorylation of ERK1/2 compared to the control. This increase was inhibited in the presence of STW5 as well as in the presence of O (p < 0.05). LOX-1 and GPR 84 are involved in experimental GERD and modulated by STW5 and O. Data support the classification of GPR84 as proinflammatory receptor with a link to the immune response. MAPKinases are differentially regulated by STW5 and O.

Keywords: Reflux disease, Multitargeting, MAP-kinases, GPR-signaling

References:

[1] Abdel-Aziz et al. A multitarget approach by STW5: the inhibition of a proinflammatory signature, the increase of membrane-bound mucins and the restoration of barrier function improves esophagitis in rats. Planta medica 2013;79:1108

[2] Ulrich-Merzenich, Zeitler et al. The lectin-like low-density lipoprotein receptor-1 as therapeutic target for atherosclerosis, inflammatory conditions and longevity. Expert Opin Ther Targets 2013;17(8):905 – 19.

[3] Abdel-Aziz et al. Receptor modulation and MAP-Kinase signaling induced by STW5 and by the proton pump inhibitor Omeprazol in a rat modell for gastroesophageal reflux disease and in HET1A-cells. UEG 2014 ABS-5267