Phosphodiesterase PDE4B2 expression in an EAE mice model

Abstract

Inflammatory responses involve cAMP and pharmacological manipulation of cAMP levels by using specific phosphodiesterase (PDE) inhibitors provokes an anti-inflammatory response. Experimental autoimmune encephalomyelitis (EAE) is an animal model of the chronic inflammatory, neurodegenerative demyelinating disease multiple sclerosis (MS). Previously we demonstrated that in the brain and spinal cord of EAE rats there was a dramatic increase in the mRNA expression levels of the PDE4B isoenzyme, solely due to the splicing mRNA variant PDE4B2. This expression was found in the infiltrating T-cells and macrophage/microglia in microvessels and brain parenchyma. We present our results on the alterations in the expression of the cAMP-specific PDE4 and of several inflammatory cytokine mRNAs in the brain and spinal cord of C57BL6 EAE mice model by neuroanatomical techniques (double in situ hybridization histochemistry and immunohistochemistry), and quantitative real time RT-PCR. We observed a PDE4B2 mRNA upregulation after the onset of the EAE model, being significant 30 days post-immunization. No changes on PDE4B3 mRNA splice variant could be detected. Double in situ hybridization and immunohistochemistry studies showed that cellular infiltrates in brain and spinal cord tissues of EAE mice are overexpressing PDE4B isoform. We found that PDE4B2 mRNA splice variant was overexpressed in T cells and macrophages/microglia in the inflammatory foci. These findings support the important and distinctive role of different PDE4 isoforms during the neuroinflammatory response produced by EAE model and its importance as a therapeutic target for the treatment of some neuroinflammatory diseases using subtype-selective PDE4B inhibitors