Noncytocidal mechanisms of action of tumor necrosis factor-alpha on human tumor cells: enhancement of HLA gene expression synergistic with interferon-gamma.
In this report, we present evidence that tumor necrosis factor alpha (TNF-alpha) exerts regulatory activity on the expression of HLA genes in human tumor cell lines at the level of mRNA expression and at a posttranscriptional level. These mechanisms are independent of direct cytotoxic/cytostatic effects, as enhancement of HLA antigen expression was observed in both sensitive cell lines and in cell lines resistant to TNF-mediated growth inhibition. In a priori HLA-negative cells, a strong TNF-alpha-mediated enhancement of the Interferon gamma (IFN-gamma) induced expression of HLA genes was revealed by Northern blot and immunofluorescence analysis. A distinct mechanism of TNF-alpha action is suggested from enhancement of constitutively expressed HLA genes. In this case, TNF-alpha raised HLA antigen density without apparent enhancement of cytoplasmic mRNA levels. This indicates that TNF-alpha influences HLA expression also at the level of translation or at a posttranslational level. TNF-alpha treatment of HLA-negative cells did not by itself result in HLA gene induction, suggesting that TNF-alpha acts as an enhancer and not as an inducer of HLA gene expression.
D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004357:Drug Synergism; D005786:Gene Expression Regulation / Q000187:drug effects; D006023:Glycoproteins / Q000494:pharmacology*; D006680:HLA Antigens / Q000235:genetics*; D015793:HLA-B7 Antigen; D006681:HLA-D Antigens / Q000235:genetics*; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D011956:Receptors, Cell Surface / Q000502:physiology; D011971:Receptors, Immunologic / Q000502:physiology; D017471:Receptors, Interferon; D018124:Receptors, Tumor Necrosis Factor; D015533:Transcriptional Activation; D014409:Tumor Necrosis Factor-alpha
D006023:Glycoproteins; D006680:HLA Antigens; D015793:HLA-B7 Antigen; D006681:HLA-D Antigens; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; D017471:Receptors, Interferon; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma