Cytokine modulation and suppression of liver injury by a novel analogue of thalidomide.
Thalidomide has been shown to reduce the production of tumor necrosis factor-alpha (TNF-alpha), a cytokine with deleterious pathophysiologic effects in various diseases. In search of thalidomide analogues with improved TNF-alpha inhibiting properties, 5-ethyl-1-phenyl-5-(3,4,5,6-tetrafluorophthalimido)barbituric acid (TFBA) was found to be superior to thalidomide. Besides TNF-alpha, TFBA also suppressed interleukin-6 and interleukin-10 production of isolated monocytes. The possibility that TFBA exerts its action by increasing levels of cAMP via inhibition of phosphodiesterase-4 activity was excluded. TFBA had no influence on T cell proliferation; neither did it inhibit TNF-alpha production in peripheral blood mononuclear cells stimulated by anti-CD3 monoclonal antibody. When applied to mice treated with D-galactosamine and lipopolysaccharide, TFBA prevented a rise in serum TNF-alpha, had no effect on interleukin-6 levels and led to an increase in interleukin-10 production. The changes in cytokine production observed in vitro and in vivo were reflected by similar changes in the mRNA expression. Moreover, TFBA significantly reduced liver transaminase levels in D-galactosamine/lipopolysaccharide-treated mice and thus efficiently protected the animals from liver injury. Thus, according to its properties, TFBA has the potential of modulating an immune response by acting as an anti-inflammatory agent.
Thiele
Andrea
A
Department of Immunobiology, Institute of Zoology, University of Leipzig, Talstrasse 33, D-04103, Leipzig, Germany.
Bang
Renate
R
Gütschow
Michael
M
Rossol
Manuela
M
Loos
Sebastian
S
Eger
Kurt
K
Tiegs
Gisa
G
Hauschildt
Sunna
S
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000378:metabolism; D000818:Animals; D001463:Barbiturates / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D056486:Chemical and Drug Induced Liver Injury / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D016207:Cytokines / Q000096:biosynthesis*; D005434:Flow Cytometry; D005688:Galactosamine; D006801:Humans; D016753:Interleukin-10 / Q000096:biosynthesis; D015850:Interleukin-6 / Q000096:biosynthesis; D008070:Lipopolysaccharides; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D010797:Phthalimides / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis; D013601:T-Lymphocytes / Q000187:drug effects / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
C475200:5-ethyl-1-phenyl-5-(3,4,5,6-tetrafluorophthalimido)barbituric acid; D001463:Barbiturates; D016207:Cytokines; D015850:Interleukin-6; D008070:Lipopolysaccharides; D010797:Phthalimides; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D005688:Galactosamine; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4