Abstract
Phosphodiesterase‐4 (PDE4) inhibitors have recently been introduced to the treatment of COPD and psoriatic arthritis. Microsomal prostaglandin E synthase‐1 (mPGES‐1) is an inducible enzyme synthesizing PGE 2, the most abundant prostanoid related to inflammation and inflammatory pain. mPGES‐1 is a potential drug target for novel anti‐inflammatory treatments aiming at an improved safety profile as compared to NSAIDs. Here we investigated the effect of the PDE4 inhibitor rolipram on the expression of mPGES‐1 in macrophages; and a potential mediator role in the process for MAP kinase phosphatase‐1 (MKP‐1) which is an endogenous factor limiting the activity of the proinflammatory MAP kinases p38 and JNK. The expression of mPGES‐1 was decreased, whereas that of MKP‐1 was enhanced by rolipram in wild‐type murine macrophages. Interestingly, rolipram did not reduce mPGES‐1 expression in peritoneal macrophages from MKP‐1‐deficient mice. A reduced phosphorylation of JNK, but not p38 MAP kinase, was specifically associated with the decreased expression of mPGES‐1. Accordingly, mPGES‐1 expression was suppressed by JNK but not p38 inhibitor. These findings underline the significance of the increased MKP‐1 expression and decreased JNK phosphorylation associated with the downregulated expression of mPGES‐1 by PDE4 inhibitors in inflammation.
Highlights
Phosphodiesterase-4 (PDE4) is a family of enzymes expressed widely in immune cells, including macrophages
To test the hypothesis that the inhibition of the expression of Microsomal prostaglandin E synthase-1 (mPGES-1) by rolipram could be mediated by MAP kinase phosphatase-1 (MKP-1), we first measured the effects of rolipram on the expression of MKP-1
We found that rolipram enhanced the expression of MKP-1 with a concomitant decrease in the expression of mPGES-1
Summary
Phosphodiesterase-4 (PDE4) is a family of enzymes expressed widely in immune cells, including macrophages. PDE4 was presented as a beneficial drug target in B-cell lymphoma, based on the findings of the anti-inflammatory properties of PDE4 inhibitors (Cooney and Aguiar 2016). Rolipram is a selective PDE4 inhibitor, the anti-inflammatory effects of which have been shown to be, at least partly, dependent on the MAP kinase phosphatase-1 (MKP-1) (Lee et al 2012; Korhonen et al 2013; Patel et al 2015). Pharmacology Research & Perspectives published by John Wiley & Sons Ltd, British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics
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