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Megan Cavet, Karen Harrington, Thomas Vollmer, Mary Richardson, Jin-Zhong Zhang; Induction of MAPK Phosphatase-1 by the Novel Selective Glucocorticoid Receptor Agonist Mapracorat Suppresses Inflammatory Signaling Pathways in Human Corneal Epithelial Cells. Invest. Ophthalmol. Vis. Sci. 2013;54(15):5399.
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© ARVO (1962-2015); The Authors (2016-present)
Prior studies demonstrated that mapracorat, a novel selective glucocorticoid receptor agonist (SEGRA), potently inhibits anti-inflammatory cytokine release in human corneal epithelial cells (HCEpiC). The aim of this study was to determine the contribution of an endogenous mitogen activated protein kinase (MAPK) regulator, MAPK phosphatase-1 (MKP-1), to mapracorat’s anti-inflammatory effects in HCEpiC.
HCEpiC were challenged with IL-β or hyperosmolarity (480 mOsm) and the levels of MKP-1 protein and MAPK phosphorylation in the presence of mapracorat were determined by Western blotting. A range of mapracorat doses were tested and dexamethasone (DEX) was used as the control. The effects of the MKP-1 inhibitor triptolide on IL-β- and 480 mOsm-induced inflammatory signaling in the presence of mapracorat was also determined.
Mapracorat alone did not stimulate the expression of MKP-1 in HCEpiC. IL-1β or 480 mOsm media significantly increased MKP-1 expression over basal levels. Following IL-β or hyperosmolar challenge, mapracorat further significantly increased MKP-1 protein levels at least 2 fold, with a peak expression at 1 h with IL-1β and 2-4 h with 480 mOsm media. The effects were not dose-dependent within the tested mapracorat concentration range (30 - 300 nM). The magnitude of increase in MKP-1 was comparable to that observed with DEX. Concomitantly to the increase in MKP-1, mapracorat also significantly reduced the levels of phosphorylated p38 and JNK MAPKs induced by IL-1β or hyperosmolarity. Triptolide-induced MKP-1 inhibition reversed the inhibitory effects of mapracorat on IL-1β or 480 mOsm-induced MAPK signaling.
These data suggest that mapracorat exerts its anti-inflammatory effects, at least in part, by increasing the expression of the MAPK deactivator MKP-1 in human corneal epithelial cells.
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