title: Attenuation of TNF production and experimentally induced inflammation by PDE4 inhibitor rolipram is mediated by MAPK phosphatase-1.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: The Immunopharmacology Research Group, University of Tampere School of Medicine and Tampere University Hospital, Tampere, Finland. riku.korhonen@uta.fi
authors.forename: Riku
authors.initials: R
authors.lastname: Korhonen
authors.forename: Tuija
authors.initials: T
authors.lastname: Hömmö
authors.forename: Tiina
authors.initials: T
authors.lastname: Keränen
authors.forename: Mirka
authors.initials: M
authors.lastname: Laavola
authors.forename: Mari
authors.initials: M
authors.lastname: Hämäläinen
authors.forename: Katriina
authors.initials: K
authors.lastname: Vuolteenaho
authors.forename: Lauri
authors.initials: L
authors.lastname: Lehtimäki
authors.forename: Hannu
authors.initials: H
authors.lastname: Kankaanranta
authors.forename: Eeva
authors.initials: E
authors.lastname: Moilanen
mesh_terms: D000818:Animals; D002351:Carrageenan / Q000494:pharmacology; D002460:Cell Line; D054638:Dual Specificity Phosphatase 1 / Q000502:physiology*; D007249:Inflammation / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D058988:Phosphodiesterase 4 Inhibitors / Q000494:pharmacology*; D020889:Rolipram / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D058988:Phosphodiesterase 4 Inhibitors; D014409:Tumor Necrosis Factor-alpha; D002351:Carrageenan; D054638:Dual Specificity Phosphatase 1; D020889:Rolipram
keywords: DUSP1; MAPK; MKP-1; PDE inhibitors; PDE4; TNF