Tumor necrosis factor (TNF) up-regulates the expression of p75 but not p55 TNF receptors, and both receptors mediate, independently of each other, up-regulation of transforming growth factor alpha and epidermal growth factor receptor mRNA.
The expression and cytokine-mediated regulation of the two different receptors for tumor necrosis factor, TNF-R-75 and TNF-R-55, was investigated in human malignant epithelial cell lines. Here we show that cells treated with TNF-alpha up-regulate the TNF-R-75 mRNA and protein levels. No changes were seen regarding the level of TNF-R-55 transcripts. Phospholipase and protein kinase C inhibitors abrogated the signal transduction pathway of TNF-mediated TNF-R-75 mRNA up-regulation which proceeded in the absence of transcriptional activation. This process was also elicited by an agonistic antibody binding specifically to TNF-R-55. Ligand binding assays using specific inhibitory antibodies showed a marked shift in active binding sites from p55 to p75 without significant changes in the total binding for TNF-alpha after up-regulation of p75 TNF-R. This ligand-induced regulation of one of the corresponding receptors has so far only been detected in malignant epithelial cells and not in hematopoietic cell lines. In our search for a specific function we were able to show that p75 is the specific receptor for TNF-mediated up-regulation of transforming growth factor alpha mRNA, whereas p55 is the signal transducer for TNF-induced up-regulation of epidermal growth factor receptor mRNA. This is the first demonstration of an exclusive function of TNF-R-75 in cells of epithelial origin.
Department of Immunology, University Hospital, Hamburg, Germany.
H
H
Kalthoff
C
C
Roeder
M
M
Brockhaus
H G
HG
Thiele
W
W
Schmiegel
D066246:ErbB Receptors / Q000235:genetics*; D005786:Gene Expression Regulation / Q000187:drug effects; D016762:Genes, fos; D006801:Humans; D066298:In Vitro Techniques; D008970:Molecular Weight; D010740:Phospholipases / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D018124:Receptors, Tumor Necrosis Factor; D015398:Signal Transduction; D012995:Solubility; D014158:Transcription, Genetic; D016211:Transforming Growth Factor alpha / Q000235:genetics* / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D015854:Up-Regulation
D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D018124:Receptors, Tumor Necrosis Factor; D016211:Transforming Growth Factor alpha; D014409:Tumor Necrosis Factor-alpha; D011494:Protein Kinases; D066246:ErbB Receptors; D010740:Phospholipases