Mapracorat, a novel selective glucocorticoid receptor agonist, inhibits hyperosmolar-induced cytokine release and MAPK pathways in human corneal epithelial cells

[摘要] Purpose: Increasing evidence suggeststhat tear hyperosmolarity is a central mechanism causing ocular surfaceinflammation and damage in dry eye disease. Mapracorat (BOL-303242-X)is a novel glucocorticoid receptor agonist currently under clinicalevaluation for use in the treatment of dry eye disease. This studyassessed the anti-inflammatory effects of mapracorat in an in vitroosmotic stress model which mimics some of the pathophysiologicalchanges seen in dry eye. Methods: Human corneal epithelial cellswere cultured in normal osmolar media (317 mOsM) or 440 mOsMhyperosmolar media for 24 h. Luminex technology was used to determinethe effect of mapracorat on hyperosmolar-induced cytokine release.Effects of mapracorat on mitogen-activated protein kinase (MAPK)phosphorylation were determined by cell based ELISA. Effects ofmapracorat on nuclear factor kappa B (NFκB) and activator protein-1(AP-1) transcriptional activity were assessed by reporter gene assay.Dexamethasone was used as a control. Results: Hyperosmolar conditions inducedrelease of the pro-inflammatory cytokines interleukin-6 (IL-6),interleukin-8 (IL-8), and monocyte chemotactic protein-1 (MCP-1) fromcultured human corneal epithelial cells, and altered thephosphorylation state of p38 and c-Jun N-terminal kinase (JNK) andtranscriptional activity of NFκB and AP-1. Incubation of cells withmapracorat inhibited hyperosmolar-induced cytokine release withcomparable activity and potency as dexamethasone. This inhibition wasreversed by the glucocorticoid receptor antagonist mifepristone(RU-486). Increased phosphorylation of p38 and JNK caused byhyperosmolarity was inhibited by mapracorat. Mapracorat alsosignificantly decreased the hyperosmolar-induced increase in NFκB andAP-1 transcriptional activity. Conclusions: Mapracorat acts as a potentanti-inflammatory agent in corneal epithelial cells challenged withosmotic stress, with comparable activity to the traditional steroiddexamethasone. These in vitro data suggest that mapracorat may beefficacious in the treatment of dry eye disease.

[学科分类] 生物化学/生物物理