cAMP specific PDE4B3 splice variants expression in male and female mouse brain during systemic inflammation

Abstract

Trabajo presentado al 10th International Congress of Neuroimmunology (ISNI) celebrado en Sitges del 26 al 30 de octubre de 2010.PDE4 represents a family of cAMP-specific PDEs consisting of four paralog genes (PDE4A-D) each distinguishable by its unique N-terminal sequence. Publications indicate that the PDE4B gene is the predominant subtype involved in inflammatory induction by lipopolysaccaride (LPS) in mouse monocytes and macrophages. Together with previous reports of expression of the three PDE4 isoforms PDE4A, PDE4B and PDE4D in oligodendrocytes (Olgs), we show that the PDE4B3 mRNA is readily present in Olgs and neurons which imply a role for this PDE4B splice variant in the central nervous system (CNS). cAMP has been shown to play an important role in protecting myelin from excitotoxic cell death and considering the sexual dimorphism in Olgs functional properties and in disease susceptibility observed for e.g. multiple sclerosis (MS) together with the alterations in the two PDE4B splice-variants (PDE4B2 and PDE4B3) mRNA expression observed after LPS administration, we focused on possible gender differences for these enzymes during the acute immediate neuroinflammatory process observed during septic shock. Furthermore, sex-related differences have been observed in the incidence and severity of sepsis in humans and also in the response towards LPS administration in rodents for several cytokines. We have analyzed the influence of an intra peritoneal LPS injection on the distribution pattern and expression levels of the PDE4B3 mRNA splicing variant in both male and female mice brain. Characterization of the cell populations involved in the PDE alterations was established by double in situ hybridization histochemistry and immunohistochemistry. By semi-quantitative analyses of the autoradiograms we observed that PDE4B3 mRNA levels showed clear changes in females 24h post-injection, whereas, in male the altered expression was less evident and peaked 8h after treatment. Furthermore, we discovered that this downregulation was reflected in a lower percentage of oligodendrocytes positive for the PDE4B3 mRNA. Knowledge about PDE4B mRNAs expression in mouse brain in both sexes and the alterations provoked by LPS administration might help us to clarify sex-related differences in the susceptibility to autoimmune diseases.Financed by 2006-10243 & SAF2009-11052. EJ is a recipient of a fellowship from Ministerio de Educación y Ciencia (BES-2007-16588).Peer Reviewe