Abstract | BACKGROUND AND PURPOSE: 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. EXPERIMENTAL APPROACH: 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. KEY 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 AND IMPLICATIONS:
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.
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Authors | Riku Korhonen, Tuija Hömmö, Tiina Keränen, Mirka Laavola, Mari Hämäläinen, Katriina Vuolteenaho, Lauri Lehtimäki, Hannu Kankaanranta, Eeva Moilanen |
Journal | British journal of pharmacology
(Br J Pharmacol)
Vol. 169
Issue 7
Pg. 1525-36
(Aug 2013)
ISSN: 1476-5381 [Electronic] England |
PMID | 23849041
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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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
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Topics |
- 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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