EFFECT OF CELL-CYCLE ON THE REGULATION OF THE CELL-SURFACE AND SECRETED FORMS OF TYPE-I AND TYPE-II HUMAN TUMOR-NECROSIS-FACTOR RECEPTORS

The cell cycle has been shown to regulate the biological effects of hu man tumor necrosis factor (TNF), but to what extent that regulation is due to the modulation of TNF receptors is not clear. In the present r eport we investigated the effect of the cell cycle on the expression o f surface and soluble TNF receptors in human histiocytic lymphoma U-93 7. Exposure to hydroxyurea, thymidine, etoposide, bisbensimide, and de mecolcine lead to accumulation of cells primarily in G(1)/S, S, S/G(2) /M, G(2)/M, and M stages of the cell cycle, respectively. While no sig nificant change in TNF receptors occurred in cells arrested in G(1)/S or S/G(2) stages, about a 50% decrease was observed in cells at M phas e of the cycle. Scatchard analysis showed a reduction in receptor numb er rather than affinity. In contrast, cells arrested at S phase (thymi dine) showed an 80% increase in receptor number. The decrease in the T NF receptors was not due to changes in cell size or protein synthesis. The increase in receptors, however, correlated with an increase in to tal protein synthesis (to 3.8-fold of the control levels). A proportio nal change was observed in the p60 and p80 forms of the TNF receptors. A decrease in the surface receptors in cells arrested in M phase corr elated with an increase in the amount of soluble receptors. The cellul ar response to TNF increased to 8- and 2-fold in cells arrested in G(1 ) and S phase, respectively; but cells at G2/M phase showed about 6-fo ld decrease in response. In conclusion, our results demonstrate that t he cell cycle plays an important role in regulation of cell-surface an d soluble TNF receptors and also in the modulation of cellular respons e. (C) 1995 Wiley-Liss, Inc.