PDE4 inhibitor rolipram inhibits the expression of microsomal prostaglandin E synthase-1 by a mechanism dependent on MAP kinase phosphatase-1.

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 PGE₂, 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. [ABSTRACT FROM AUTHOR]