The phosphodiesterase i.v. inhibitor rolipram in vitro reduces the numbers of MBP-reactive IFN-gamma and TNF-alpha mRNA expressing blood mononuclear cells in patients with multiple sclerosis.
The inflammatory nature of multiple sclerosis (MS) implicates the participation of cytokines as immune response mediators. Targeting the cytokine balance by downregulating proinflammatory cytokines and/or upregulating immunosuppressive cytokines could benefit patients with MS. This article reports on the in vitro effects of the phosphodiesterase i.v. inhibitor Rolipram on the production of pro- and anti-inflammatory cytokines in MS and, for reference, in myasthenia gravis (MG). Blood mononuclear cells (MNC) were cultured in the presence of the organ-specific autoantigens myelin basic protein (MBP) or acetylcholine receptor (AChR), and in the absence of antigens, with and without Rolipram. In situ hybridization with synthetic oligonucleotide probes was used to detect and enumerate blood MNC expressing IFN-gamma, TNF-alpha, LT, TGF-beta, IL-4, and IL-10 mRNA. Numbers of MNC-secreting IFN-gamma and IL-4 in blood blood were examined by ELISPOT assays. Rolipram reduced the numbers of MBP-reactive IFN-gamma- and TNF-alpha mRNA-expressing blood MNC in MS, and numbers of AChR-reactive IFN-gamma-, TNF-alpha-, and LT mRNA-positive cells in MG. In contrast, expression of the Th2 cell related IL-4 and the anti-inflammatory IL-10, and TGF-beta was not affected. These data support a role for Rolipram in the treatment of diseases such as MS.
Division of Neurology, Karolinska Institute, Huddinge University Hospital, Stockholm, Sweden.
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Navikas
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Matusevicius
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Söderström
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Pirskanen
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Fredrikson
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D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors; D000328:Adult; D000368:Aged; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D002478:Cells, Cultured; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D005260:Female; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis* / Q000097:blood; D016753:Interleukin-10 / Q000096:biosynthesis / Q000097:blood; D015847:Interleukin-4 / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000097:blood* / Q000188:drug therapy*; D009157:Myasthenia Gravis / Q000097:blood / Q000188:drug therapy; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D011760:Pyrrolidinones / Q000494:pharmacology*; D012333:RNA, Messenger / Q000097:blood*; D020889:Rolipram; D016212:Transforming Growth Factor beta / Q000096:biosynthesis / Q000097:blood; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000378:metabolism
D000894:Anti-Inflammatory Agents, Non-Steroidal; D010726:Phosphodiesterase Inhibitors; D011760:Pyrrolidinones; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D015847:Interleukin-4; D007371:Interferon-gamma; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D020889:Rolipram