ABSTRACT
In multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE) the cytokines tumour necrosis factor-alpha (TNF), lymphotoxin-alpha (LT), and interferon-gamma (IFN-gamma) are of central pathogenetic importance. A therapy capable of stopping neurological deterioration in MS patients is not yet available. Here, we report that rolipram, a selective type IV phosphodiesterase inhibitor, stereospecifically suppresses the production of TNF/LT and less strongly also IFN-gamma in human and rat auto-reactive T cells. Moreover, we show that rolipram is an effective treatment for EAE. Rolipram has extensively been studied in humans for the treatment of depression, but has not yet been marketed. The data presented here identify rolipram as potential therapy for multiple sclerosis and provoke the immediate initiation of clinical trials.
Subject(s)
Antidepressive Agents/pharmacology , CD4-Positive T-Lymphocytes/metabolism , Encephalomyelitis, Autoimmune, Experimental/prevention & control , Phosphodiesterase Inhibitors/pharmacology , Pyrrolidinones/pharmacology , Tumor Necrosis Factor-alpha/biosynthesis , Animals , CD4-Positive T-Lymphocytes/drug effects , Cells, Cultured , Humans , Interferon-gamma/biosynthesis , Multiple Sclerosis/drug therapy , Rats , Rats, Inbred Lew , Rolipram , StereoisomerismABSTRACT
In rat hepatocyte primary cultures recombinant interleukin 1 was found to stimulate alpha 2-macroglobulin synthesis, whereas albumin synthesis was decreased. Although recent experiments gave evidence that a hepatocyte-stimulating factor distinct from interleukin 1 must exist, we conclude that interleukin 1 exerts a direct effect on hepatocytes by inducing acute-phase protein synthesis.
Subject(s)
Interleukin-1/pharmacology , Liver/metabolism , alpha-Macroglobulins/biosynthesis , Albumins/biosynthesis , Animals , Cells, Cultured , Chemical Precipitation , Immunochemistry , Kinetics , Mice , RatsABSTRACT
Turpentine injection into rats elicits enhanced secretion of acute phase proteins including alpha 2-macroglobulin (alpha 2M). Hypophysectomized rats, however, do not respond in this way unless dexamethasone is given together with turpentine. On the other hand, dexamethasone injection alone did not result in an induction of alpha 2M synthesis. When a medium of Kupffer cell cultures was added to hepatocytes, a dose-dependent stimulation of alpha 2M synthesis of up to 4-fold after 10-12 h was observed. However, the presence of low concentrations (10(-9)M) of dexamethasone was essential for the stimulatory effect. We conclude that the acute phase induction of alpha 2M in hepatocytes requires the synergistic action of glucocorticoids and a non-dialysable factor secreted by Kupffer cells.
