Background/Purpose: MAP kinase phosphatase-1 (MKP-1) is a nuclear tyrosine/threonine phosphatase that limits p38 MAP kinase activity. MKP-1 KO mice display excessive inflammatory response, and exhibit increased disease severity and more extensive bone destruction in experimental arthritis models. Anti-inflammatory effects of glucocorticoids are partly mediated by increased MKP-1 expression. Phosphodiesterase (PDE) 4 is expressed in several inflammatory and immune cells, and it hydrolyzes cAMP to 5’AMP down-regulating cAMP signalling in cells. PDE4 inhibitors are under investigation for treatment of arthritis, and they have already entered the clinics in the treatment of COPD as an anti-inflammatory remedy. In the present study, we found that a PDE4 inhibitor rolipram enhanced MKP-1 expression which was involved in the anti-inflammatory effects of rolipram.

Methods: The effect of MKP-1 and a PDE4 inhibitor rolipram on inflammatory gene expression was investigated in mouse J774 and human THP-1 macrophage cell lines, and in primary mouse peritoneal macrophages (PM) from wild-type (WT) and MKP-1(–/–) mice. In cell lines, MKP-1 expression was silenced by siRNA. We also investigated the effect of rolipram on carrageenan-induced paw inflammation in WT and MKP-1(–/–) mice.

Results: TNF and IL-6 production was increased in macrophages with impaired MKP-1 (that is in cells transfected with MKP-1 siRNA or macrophages from MKP-1 KO mice), and it was related to increased p38 MAP kinase phosphorylation. p38 MAP kinase phosphorylation was inhibited by rolipram and by a cAMP analog 8-Br-cAMP. LPS-induced MKP-1 expression was enhanced by rolipram, by a non-selective PDE inhibitor IBMX and by 8-Br-cAMP in J774 and THP-1 cells and in PMs. Rolipram, IBMX and 8-Br-cAMP also inhibited TNF production in J774 and THP-1 cells. p38 MAP kinase inhibitor BIRB 796 inhibited TNF production in macrophages, as expected. Rolipram inhibited TNF production in PMs from WT mice (63% inhibition) but, interestingly, the inhibition of TNF production by rolipram was greatly attenuated (27% inhibition) in PMs from MKP-1(–/–) mice. Furthermore, rolipram attenuated carrageenan-induced paw inflammation in WT but not in MKP-1(–/–) mice.

Conclusion:

The results showed that a PDE4 inhibitor rolipram suppressed p38 MAP kinase pathway, and inhibited TNF production and carrageenan-induced inflammation, and these effects were mediated by MKP-1. The results suggest that the anti-inflammatory effects of PDE4 inhibitors are, at least partly, mediated by MKP-1. The findings emphasize MKP-1 as a potential mediator of anti-inflammatory drug effects. Compounds that enhance MKP-1 expression and/or MKP-1 activity hold potential as novel anti-inflammatory drugs.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/anti-inflammatory-effects-of-phosphodiesterase-4-inhibition-are-mediated-by-mitogen-activated-protein-kinase-phosphatase-1/