The synergistic cytocidal effect produced by immune interferon and tumor necrosis factor in HT-29 cells is associated with inhibition of rRNA processing and (2',5') oligo (A) activation of RNase L.
The cytocidal activity of human immune interferon (IFN-tau) in combination with recombinant tumor necrosis factor-alpha (TNF) was assessed in human colon carcinoma cell line HT-29. IFN-tau or TNF alone reduced cell viability by 15-20%, but in combination produced a synergistic cytotoxic effect which inhibited colony formation by 55-85%. TNF impaired the processing of ribosomal precursor 45S RNA to 32S RNA which resulted in the selective inhibition of 28S rRNA. Both TNF and IFN-tau induced the activity of (2',5') oligo (A) synthetase and produced selective degradation of 28S rRNA, effects possibly related to the (2',5') oligo (A)-dependent activation of RNase L. The combination of IFN-tau and TNF resulted in a marked reduction in the labeling of ribosomal precursor RNAs as well as mature rRNA. These results demonstrate that the posttranscriptional and processing effects of IFN-tau and TNF are related to the enhanced cytotoxicity by this combination of cytokines.
D015088:2',5'-Oligoadenylate Synthetase / Q000378:metabolism; D000227:Adenine Nucleotides / Q000378:metabolism; D000906:Antibodies; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003110:Colonic Neoplasms / Q000235:genetics / Q000473:pathology*; D004261:DNA Replication / Q000187:drug effects; D004722:Endoribonucleases / Q000378:metabolism; D006801:Humans; D007370:Interferon Type I / Q000276:immunology; D007371:Interferon-gamma / Q000494:pharmacology*; D009843:Oligoribonucleotides / Q000378:metabolism; D012313:RNA / Q000096:biosynthesis; D012335:RNA, Ribosomal / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D000227:Adenine Nucleotides; D000906:Antibodies; D007370:Interferon Type I; D009843:Oligoribonucleotides; D012335:RNA, Ribosomal; D011956:Receptors, Cell Surface; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; C023505:2',5'-oligoadenylate; D012313:RNA; D007371:Interferon-gamma; D015088:2',5'-Oligoadenylate Synthetase; D004722:Endoribonucleases; C031956:2-5A-dependent ribonuclease