ROLE OF THE 75 KD-RECEPTORS AND 55 KD-RECEPTORS IN TUMOR-NECROSIS-FACTOR MEDIATED CYTOTOXICITY AND ITS REGULATION BY DEXAMETHASONE AND BY 1,25-DIHYDROXYVITAMIN-D(3) IN U937 CELLS

The respective role of p55 and of p75 TNF receptors in mediating the c onstitutive or the regulated cytotoxic response of U937 cells was disc riminated using monoclonal antibodies directed against each receptor t ype, respectively htr-9 and utr-1. Cytotoxicity was mediated by the p5 5 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 requ ired to be present for rTNF-alpha to be active. It increased the maxim al response whether toxicity was mediated through only p55 or both p55 and p75 receptors, without changing the respective EC50 values for rT NF-alpha. Therefore dexamethasone did not affect the interactions betw een p55 and p75 receptors nor between these receptors and their ligand , suggesting that it regulates the cytotoxicity at a post-receptor lev el. 1,25-dihydroxyvitamin D3 drove the promonocytic U937 cells resista nt to rTNF-alpha by short-term effect. Comparing the effect of 1,25-di hydroxyvitamin D3 and 1,25-dihydroxyvitamin D3 derivatives on the cyto toxicity to their effect on cell surface receptor expression, revealed that the capacity to induce resistance to rTNF-alpha was restricted t o those steroids which down-regulated the p55 receptors. Therefore, re sistance to rTNF-alpha could be related to an early effect of 1,25-dih ydroxyvitamin D3 on p55 receptors. Finally, the results suggest that d examethasone and 1,25-dihydroxyvitamin D3 regulate TNF-alpha induced c ytotoxicity by affecting processes probably related to the functions o f the p55 receptors.