Role of the 75 kD- and 55 kD-receptors in tumour necrosis factor mediated cytotoxicity and its regulation by dexamethasone and by 1,25-dihydroxyvitamin D3 in U937 cells.
The respective role of p55 and of p75 TNF receptors in mediating the constitutive or the regulated cytotoxic response of U937 cells was discriminated using monoclonal antibodies directed against each receptor type, respectively htr-9 and utr-1. Cytotoxicity was mediated by the p55 receptors. The p75 receptors were also implicated as it reduced 100 fold the maximal active dose of rTNF-alpha and 15 fold the EC50 value. Dexamethasone potentiated and 1,25-dihydroxyvitamin D3 abolished rTNF-alpha induced cell growth arrest and toxicity. Dexamethasone was required to be present for rTNF-alpha to be active. It increased the maximal response whether toxicity was mediated through only p55 or both p55 and p75 receptors, without changing the respective EC50 values for rTNF-alpha. Therefore dexamethasone did not affect the interactions between p55 and p75 receptors nor between these receptors and their ligand, suggesting that it regulates the cytotoxicity at a post-receptor level. 1,25-dihydroxyvitamin D3 drove the promonocytic U937 cells resistant to rTNF-alpha by short-term effect. Comparing the effect of 1,25-dihydroxyvitamin D3 and 1,25-dihydroxyvitamin D3 derivatives on the cytotoxicity to their effect on cell surface receptor expression, revealed that the capacity to induce resistance to rTNF-alpha was restricted to those steroids which down-regulated the p55 receptors. Therefore, resistance to rTNF-alpha could be related to an early effect of 1,25-dihydroxyvitamin D3 on p55 receptors. Finally, the results suggest that dexamethasone and 1,25-dihydroxyvitamin D3 regulate TNF-alpha induced cytotoxicity by affecting processes probably related to the functions of the p55 receptors.
Chambaut-Guérin
A M
AM
INSERM U282, Hôpital Henri Mondor, Créteil, France.
Guerrier
M
M
Thomopoulos
P
P
D002117:Calcitriol / Q000031:analogs & derivatives / Q000494:pharmacology*; D003907:Dexamethasone / Q000494:pharmacology*; D004357:Drug Synergism; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000473:pathology; D015735:Mifepristone / Q000494:pharmacology; D018124:Receptors, Tumor Necrosis Factor / Q000145:classification / Q000187:drug effects*; D011994:Recombinant Proteins / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D018124:Receptors, Tumor Necrosis Factor; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D015735:Mifepristone; D003907:Dexamethasone; D002117:Calcitriol