Cytokine modulation and suppression of liver injury by a novel analogue of thalidomide.
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Cytokine modulation and suppression of liver injury by a novel analogue of thalidomide. / Thiele, Andrea; Bang, Renate; Gütschow, Michael; Rossol, Manuela; Loos, Sebastian; Eger, Kurt; Tiegs, Gisa; Hauschildt, Sunna.
In: EUR J PHARMACOL, Vol. 453, No. 2-3, 2-3, 2002, p. 325-334.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Cytokine modulation and suppression of liver injury by a novel analogue of thalidomide.
AU - Thiele, Andrea
AU - Bang, Renate
AU - Gütschow, Michael
AU - Rossol, Manuela
AU - Loos, Sebastian
AU - Eger, Kurt
AU - Tiegs, Gisa
AU - Hauschildt, Sunna
PY - 2002
Y1 - 2002
N2 - 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.
AB - 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.
KW - Animals
KW - Humans
KW - Mice
KW - Mice, Inbred BALB C
KW - Lymphocyte Activation
KW - Flow Cytometry
KW - Lipopolysaccharides
KW - Galactosamine
KW - RNA, Messenger/biosynthesis
KW - Interleukin-6/biosynthesis
KW - Tumor Necrosis Factor-alpha/biosynthesis
KW - 3',5'-Cyclic-AMP Phosphodiesterases/metabolism
KW - Barbiturates/pharmacology
KW - Cell Division/drug effects
KW - Cyclic Nucleotide Phosphodiesterases, Type 4
KW - Cytokines/biosynthesis
KW - Drug-Induced Liver Injury/drug therapy/etiology/metabolism
KW - Interleukin-10/biosynthesis
KW - Monocytes/drug effects/metabolism
KW - Phthalimides/pharmacology
KW - T-Lymphocytes/drug effects/pathology
KW - Animals
KW - Humans
KW - Mice
KW - Mice, Inbred BALB C
KW - Lymphocyte Activation
KW - Flow Cytometry
KW - Lipopolysaccharides
KW - Galactosamine
KW - RNA, Messenger/biosynthesis
KW - Interleukin-6/biosynthesis
KW - Tumor Necrosis Factor-alpha/biosynthesis
KW - 3',5'-Cyclic-AMP Phosphodiesterases/metabolism
KW - Barbiturates/pharmacology
KW - Cell Division/drug effects
KW - Cyclic Nucleotide Phosphodiesterases, Type 4
KW - Cytokines/biosynthesis
KW - Drug-Induced Liver Injury/drug therapy/etiology/metabolism
KW - Interleukin-10/biosynthesis
KW - Monocytes/drug effects/metabolism
KW - Phthalimides/pharmacology
KW - T-Lymphocytes/drug effects/pathology
M3 - SCORING: Journal article
VL - 453
SP - 325
EP - 334
JO - EUR J PHARMACOL
JF - EUR J PHARMACOL
SN - 0014-2999
IS - 2-3
M1 - 2-3
ER -
