Suppression of tumor necrosis factor secretion from white blood cells by synthetic antisense phosphorothioate oligodeoxynucleotides.
In this ex vivo, rather than in vitro, experiment, a synthetic antisense oligodeoxynucleotide was tested to suppress tumor necrosis factor - alpha(TNF) secretion from lipopolysaccharide-stimulated white blood cells. Antisense oligomer showed significant and specific suppressive effect to the secretion of TNF at concentrations of 1.0 and 10 microM. At the concentration of 1 microM, there were 68.4 and 63.9% suppression of TNF secretion at 2 and 24 h after resuspension of blood cells. At the concentration of 10 microM, the suppressions were slightly higher than those at 1 microM, which were 71.8 and 76.2%, respectively. A 50%-matched scrambler showed suppressive effect only at 10 microM concentration, and the suppression only occurred at 2 and 24 h after incubation. Sense oligomer showed no suppressive effects at any of the concentrations. The specificity of this oligomer was documented by dose-effect phenomenon, sequence-dependent suppression and absence of effect on the synthesis of another cytokine (interleukin-6). A series of parallel studies was performed and showed that all three oligomers at any concentration tested had no effect on the interleukin-6 secretion after LPS stimulation.In conclusion, properly designed antisense oligodeoxynucleotide can significantly and specifically suppress the secretion of TNF by blood cells in an ex vivo system and it may be a good "information" drug to treat diseases that are caused by over production of TNF.
Hu
R H
RH
Department of Surgery, National Taiwan University Hospital, 7 Chung-Shan South Road, Taipei, Taiwan.
Chu
S H
SH
D003513:Cycloheximide / Q000494:pharmacology; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis; D007962:Leukocytes / Q000187:drug effects / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D013268:Stimulation, Chemical; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000096:biosynthesis
D015850:Interleukin-6; D008070:Lipopolysaccharides; D016376:Oligonucleotides, Antisense; D011500:Protein Synthesis Inhibitors; D014409:Tumor Necrosis Factor-alpha; D003513:Cycloheximide