Involvement of 26-kDa membrane-bound tumour necrosis factor precursor in bidirectional feedback regulation on 17-kDa tumour necrosis factor production after stimulation by lipopolysaccharide.

The authors have previously shown that 26-kDa membrane-bound tumour necrosis factor precursor (proTNF) on the cell-surface of primed human monocytic cell line THP-1 is involved in positive feedback regulation of lipopolysaccharide (LPS)-dependent TNF-production. Here, we provide direct evidence for modulation of responsiveness of the THP-1 cells against LPS by membrane-bound pro-TNF. When THP-1 cells were cocultivated with a heterogeneous cell line (proTNF/3T3 cells) which constitutively expressed membrane-bound proTNF, LPS-dependent TNF-production by THP-1 cells was significantly suppressed and the normal level was restored by the presence of anti-TNF antibody during cocultivation. The proTNF-3T3-induced decline of TNF-production of THP-1 was observed primarily at the mRNA level, although no difference was observed in the mRNA level of interleukin 1 beta, another LPS-inducible cytokine. These results suggest that proTNF could also be involved in the negative feedback regulation of LPS-dependent TNF-production through cell-to-cell contact. The augmentation of LPS-dependent TNF-production accompanied by the production of endogenous proTNF induced by exogenous agent was inhibited by protein kinase C inhibitor, whereas proTNF/3T3-induced suppression of TNF-production could not be restored to the normal level. It thus seems possible that proTNF might act on macrophages as a bidirectional regulator of its production by THP-1 cells depending on co-induced signals.