Int Immunopharmacol
The Immunopharmacology Research Group, Faculty of Medicine and Health Technology, Tampere University and Tampere University Hospital, Tampere, Finland. Electronic address:
Published: June 2019
Objectives: Microsomal prostaglandin E synthase-1 (mPGES-1) catalyses the formation of PGE in inflammatory tissues. It is considered a potential drug target in inflammatory conditions to achieve clinical benefits comparable to NSAIDs with a better tolerability. Inhibitors of mPGES-1 are under development but the pharmacological regulation of mPGES-1 expression remains poorly known. MAP kinase phosphatase-1 (MKP-1) is an enzyme that limits the activity of pro-inflammatory MAP kinases p38 and JNK. In the present study, we discovered that dexamethasone down-regulates mPGES-1 expression in articular chondrocytes in an MKP-1 and p38 kinase dependent manner.
Methods: Primary human chondrocytes were isolated from cartilage samples obtained from osteoarthritis (OA) patients undergoing knee replacement surgery. Primary mouse chondrocytes were isolated from cartilage samples of MKP-1 deficient (knock-out, KO) and corresponding wild type (WT) mice. Expression of mPGES-1 and MKP-1 were measured by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and Western blot, and MAP kinase phosphorylation by Western blot.
Results: Dexamethasone inhibited the expression of mPGES-1 in primary human chondrocytes and in chondrocytes from wild type but not from MKP-1 deficient mice. Dexamethasone enhanced MKP-1 expression in chondrocytes from wild type mice as well as in primary human OA chondrocytes. Dexamethasone induced the dephosphorylation of both p38 and JNK, whereas mPGES-1 expression was downregulated by selective inhibitors of p38 only.
Conclusions: The results show that MKP-1 is a crucial mediator of pharmacological control of inflammatory mPGES-1 expression by glucocorticoids, and underline MKP-1 as a potential anti-inflammatory drug target.
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http://dx.doi.org/10.1016/j.intimp.2019.03.014 | DOI Listing |
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Department of Parasitology, Chung Shan Medical University, Taichung, 402, Taiwan.
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Department of Biotechnology and Life Science, Tokyo University of Agriculture and Technology, 2-24-16 Nakacho, Koganei-shi, Tokyo 184-8588, Japan.
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