High Expression of IL-1RI and EP2 Receptors in the IL-1β/COX-2 Pathway and a New Alternative to Non-Steroidal Drugs—Osthole in Inhibition COX-2

摘要

Background: Osthole (7-methoxy-8-isopentenylcoumarin) is natural coumarin isolated from the fruit of Cnidium monnieri (L.) Cusson, which is commonly used in medical practice of traditional Chinese medicine (TCM) in various diseases including allergies and asthma disorders. Purpose: Osthole was tested for the anti-histamine, anti-allergic, and inhibitory effects of COX-2 (cyclooxygenase-2) in children with diagnosed allergies. Additionally, we hypothesize that stated alterations in children with diagnosed allergies including increased expression of interleukin 1-β receptor type 1 (IL-1 type I) and E-prostanoid (EP) 2 receptors, as well as raised expression, production, and activity of COX-2 and IL-1β in incubated medium are approximately connected. Furthermore, we establish the mechanisms included in the changed regulation of the COX-2 pathway and determine whether osthole may be COX-2 inhibitor in peripheral blood mononuclear cells (PBMCs). Method: PBMCs were obtained from peripheral blood of healthy children (control, n = 28) and patients with diagnosed allergies (allergy, n = 30). Expression of the autocrine loop components regulating PGE2 production and signaling namely IL-1 type I receptor (IL-1RI), cyclooksygenaze-2 (COX-2), E-prostanoid (EP) 2, and also histamine receptor-1 (HRH-1) was assessed at baseline and after stimulation with histamine, osthole, and a mixture of histamine/osthole 1:2 (v/v). This comprised the expression of histamine receptor 1 (HRH-1), IL-1RI, COX-2, EP2 receptor, and the secretion of IL-1β and COX-2 in cultured media and sera. Results: Compared with control group, basal mRNA expression levels of HRH-1, IL-1RI, COX-2, and EP2 were higher in the allergy group. Histamine-induced EP2 and COX-2 expression mRNA levels were also increased. Conclusions: Osthole successively inhibits PGE2 and COX-2 mRNA expression. Furthermore, osthole reduces the secretion of COX-2 protein in signaling cellular mechanisms. Changed EP2 expression in children with allergies provides higher IL-1RI induction, increasing IL-1β capacity to increase COX-2 expression. This effects in higher PGE2 production, which in turn increases its capability to induce IL-1RI.