Protective effect of rolipram in experimental autoimmune neuritis: Protection is associated with down-regulation of IFN-gamma and inflammatory chemokines as well as up-regulation of IL-4 in peripheral nervous system

Rolipram, a phosphodiesterase type 4 inhibitor, is reported to have anti-in flammatory effects. It can markedly downregulate antigen-driven T cell prol iferation and suppress TNF-alpha and TNF-beta production in vitro and in vi vo, which have led to its use in the treatment of a number of autoimmune di sorders including experimental autoimmune encephalomyelitis (EAE) and exper imental autoimmune neuritis (EAN). EAN is a CD4(+) T cell-mediated demyelin ating autoimmune disease of peripheral nervous system (PNS) that represents an animal model for the study of the immunopathogenesis and immunotherapy of Guillain-Barre syndrome (GBS) in human. In the previous study, we report ed that suppression of EAN by Rolipram was associated with down-regulated m yelin antigen-induced T cell responses as well as downregulated IFN-gamma a nd TNF-alpha production. Here we report that EAN induced in Lewis rats by i noculation with the PNS P2 protein peptide 57-81 and Freund's complete adju vant (FCA), was strongly suppressed by Rolipram administered twice daily in traperitoneally from day 9 post immunization (p.i.), i.e. after onset of cl inical EAN to day 18 p.i. This clinical effect was associated with dose-dep endent down-regulated production of IFN-gamma and the chemokines macrophage inflammatory protein-1 alpha (MIP-1 alpha), MIP-2 and monocyte chemotactic protein-1 (MCP-1) as well as up-regulated IL-4 production in sciatic nerve sections from Rolipram-treated EAN rats at maximum of clinical EAN, i.e. o n day 14 p.i,. These findings suggest that Rolipram may be useful in certai n T cell-dependent autoimmune diseases and inflammatory neuropathies. These observations call for further studies on the potential role of Rolipram in the treatment of autoimmune diseases.