Cytokine modulation and suppression of liver injury by a novel analogue of thalidomide

• Published in: European journal of pharmacology Vol. 453; no. 2-3; pp. 325 - 334
• Main Authors: Thiele, Andrea, Bang, Renate, Gütschow, Michael, Rossol, Manuela, Loos, Sebastian, Eger, Kurt, Tiegs, Gisa, Hauschildt, Sunna
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier B.V 25.10.2002; Elsevier
• Subjects: 3',5'-Cyclic-AMP Phosphodiesterases - metabolism; Animals; Barbiturates - pharmacology; Biological and medical sciences; Bones, joints and connective tissue. Antiinflammatory agents; Cell Division - drug effects; Chemical and Drug Induced Liver Injury - drug therapy; Chemical and Drug Induced Liver Injury - etiology; Chemical and Drug Induced Liver Injury - metabolism; Cyclic Nucleotide Phosphodiesterases, Type 4; Cytokine modulation; Cytokines - biosynthesis; Flow Cytometry; Galactosamine; Humans; Immunomodulators; Interleukin-10 - biosynthesis; Interleukin-6 - biosynthesis; Lipopolysaccharides; Liver injury; Lymphocyte Activation; Medical sciences; Mice; Mice, Inbred BALB C; Monocytes - drug effects; Monocytes - metabolism; Pharmacology. Drug treatments; Phthalimides - pharmacology; RNA, Messenger - biosynthesis; suppression; T-Lymphocytes - drug effects; T-Lymphocytes - pathology; Thalidomide analogue; Tumor Necrosis Factor-alpha - biosynthesis; Cytokine modulation; Thalidomide analogue; Liver injury; Biological fluid; Hepatoprotector; Hepatic disease; Blood; Interleukin 6; Prevention; Mechanism of action; Thalidomide; Tumor necrosis factor α; Human; Healthy subject; Monocyte; Cytokine; Rodentia; Antiinflammatory agent; Cyclic AMP; In vitro; Biological activity; Immunomodulator; In vivo; Vertebrata; Mammalia; Mouse; Analog; Animal; Interleukin 10; Digestive diseases
• DOI: 10.1016/S0014-2999(02)02423-8
• ISSN: 0014-2999

Thalidomide has been shown to reduce the production of tumor necrosis factor-α (TNF-α), a cytokine with deleterious pathophysiologic effects in various diseases. In search of thalidomide analogues with improved TNF-α inhibiting properties, 5-ethyl-1-phenyl-5-(3,4,5,6-tetrafluorophthalimido)barbituric acid (TFBA) was found to be superior to thalidomide. Besides TNF-α, 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-α 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-α, 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.