DIVERGENT RESPONSES OF HUMAN ASTROCYTOMA AND NONNEOPLASTIC ASTROCYTES TO TUMOR-NECROSIS-FACTOR-ALPHA INVOLVE THE 55-KDA TUMOR-NECROSIS-FACTOR RECEPTOR

The effects of tumor necrosis factor (TNF) on DNA synthesis, proliferation, and induction of gene/protein expression of TNF were compared in neoplastic and non-neoplastic adult human astrocytes. Previously, we demonstrated that TNF induced proliferative responses in non-neoplastic adult human astrocytes. In astrocytoma cells, however, TNF elicited both proliferative and cytostatic responses depending upon cell density and TNF concentration. This bimodal effect persisted even in a homogeneous, cloned astrocytoma cell line (STT-9C), and was inhibitable by neutralizing antibody to TNF. TNF treatment enhanced expression of TNF mRNA in astrocytoma cells but not in non-neoplastic astrocytes, and cell-associated or secreted TNF was not detectable in any culture. The involvement of receptors in astrocyte responses to TNF was examined in serological studies using monoclonal antibodies Utr-1 to the 75 kDa, and Htr-9 to the 55 kDa TNF receptor. Antibody to the 55 kDa TNF receptor alone was able to mimic the effects of TNF in both neoplastic and non-neoplastic astrocyte cultures while antibody to the 75 kDa TNF receptor had no effect. These data indicate that the bimodal actions of TNF on human astrocytoma cells as well as the stimulatory effects on non-neoplastic adult astrocytes are regulated at least in part by the 55 kDa TNF receptor. Astrocyte TNF receptors, however, do not appear to constitute part of an autocrine growth pathway in either non-neoplastic or neoplastic human astrocytes.