Attenuation of TNF production and experimentally induced inflammation by PDE4 inhibitor rolipram is mediated by MAPK phosphatase-1.

3',5'-Cyclic nucleotide PDE4 is expressed in several inflammatory and immune cells, and PDE4 catalyses the hydrolysis of cAMP to 5'AMP, down-regulating cAMP signalling in cells. MAPK phosphatase-1 (MKP-1) is an endogenous p38 MAPK signalling suppressor and limits inflammatory gene expression and inflammation. In the present study, we investigated the effect of a PDE4 inhibitor rolipram on MKP-1 expression and whether MKP-1 is involved in the anti-inflammatory effects of rolipram.
The effect of rolipram on TNF production was investigated in J774 mouse macrophage cell line and in primary mouse peritoneal macrophages (PM) from wild-type (WT) and MKP-1(-/-) mice. We also investigated the effect of rolipram on carrageenan-induced paw inflammation in WT and MKP-1(-/-) mice.
MKP-1 expression was enhanced by rolipram, by a non-selective PDE inhibitor IBMX and by a cAMP analogue 8-Br-cAMP in J774 cells and in PM. Enhanced MKP-1 mRNA expression by rolipram was reversed by a PKA inhibitor. Rolipram, IBMX and 8-Br-cAMP also inhibited TNF production in activated macrophages. Accordingly, rolipram inhibited TNF production in PMs from WT mice but, interestingly, not in PMs from MKP-1(-/-) mice. Furthermore, rolipram attenuated carrageenan-induced paw inflammation in WT but not in MKP-1(-/-) mice.
PDE4 inhibitor rolipram was found to enhance the expression of MKP-1, and MKP-1 mediated, at least partly, the anti-inflammatory effects of PDE4 inhibition. The results suggest that compounds that enhance MKP-1 expression and/or MKP-1 activity hold potential as novel anti-inflammatory drugs.
AuthorsRiku Korhonen, Tuija Hömmö, Tiina Keränen, Mirka Laavola, Mari Hämäläinen, Katriina Vuolteenaho, Lauri Lehtimäki, Hannu Kankaanranta, Eeva Moilanen
JournalBritish journal of pharmacology (Br J Pharmacol) Vol. 169 Issue 7 Pg. 1525-36 (Aug 2013) ISSN: 1476-5381 [Electronic] England
PMID23849041 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Copyright© 2013 The Authors. British Journal of Pharmacology © 2013 The British Pharmacological Society.
Chemical References
  • Phosphodiesterase 4 Inhibitors
  • Tumor Necrosis Factor-alpha
  • Carrageenan
  • Dual Specificity Phosphatase 1
  • Rolipram
  • Animals
  • Carrageenan (pharmacology)
  • Cell Line
  • Dual Specificity Phosphatase 1 (physiology)
  • Inflammation (chemically induced, genetics, metabolism)
  • Macrophages (metabolism)
  • Mice
  • Mice, Inbred C57BL
  • Phosphodiesterase 4 Inhibitors (pharmacology)
  • Rolipram (pharmacology)
  • Signal Transduction (drug effects)
  • Tumor Necrosis Factor-alpha (metabolism)

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