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Attenuation of TNF production and experimentally induced inflammation by PDE 4 inhibitor rolipram is mediated by MAPK phosphatase‐1
Author(s) -
Korhonen Riku,
Hömmö Tuija,
Keränen Tiina,
Laavola Mirka,
Hämäläinen Mari,
Vuolteenaho Katriina,
Lehtimäki Lauri,
Kankaanranta Hannu,
Moilanen Eeva
Publication year - 2013
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.12189
Subject(s) - rolipram , phosphodiesterase inhibitor , phosphodiesterase , inflammation , tumor necrosis factor alpha , ibmx , chemistry , endocrinology , pharmacology , medicine , biology , biochemistry , forskolin , enzyme , receptor
Background and Purpose 3′,5′‐Cyclic nucleotide PDE 4 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‐ B r‐ cAMP in J774 cells and in PM . Enhanced MKP ‐1 mRNA expression by rolipram was reversed by a PKA inhibitor. Rolipram, IBMX and 8‐ B r‐ 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.