INVOLVEMENT OF 26-KDA MEMBRANE-BOUND TUMOR-NECROSIS-FACTOR PRECURSOR IN BIDIRECTIONAL FEEDBACK-REGULATION ON 17-KDA TUMOR-NECROSIS-FACTOR PRODUCTION AFTER STIMULATION BY LIPOPOLYSACCHARIDE

The authors have previously shown that 26-kDa membrane-bound tumour ne crosis factor precursor (proTNF) on the cell-surface of primed human m onocytic cell line THP-1 is involved in positive feedback regulation o f lipopolysaccharide (LPS)-dependent TNF-production, Here, we provide direct evidence for modulation of responsiveness of the THP-1 cells ag ainst LPS by membrane-bound proTNF, When THP-1 cells were cocultivated with a heterogeneous cell line (proTNF/3T3 cells) which constitutivel y expressed membrane-bound proTNF, LPS-dependent TNF-production by THP -1 cells was significantly suppressed and the normal level was restore d by the presence of anti-TNF antibody during cocultivation. The proTN F-3T3-induced decline of TNF-production of THP-1 was observed primaril y at the mRNA level, although no difference was observed in the mRNA l evel of interleukin 1 beta, another LPS-inducible cytokine, These resu lts suggest that proTNF could also be involved in the negative feedbac k regulation of LPS-dependent TNF-production through cell-to-cell cont act, The augmentation of LPS-dependent TNF-production accompanied by t he production of endogenous proTNF induced by exogenous agent was inhi bited by protein kinase C inhibitor, whereas proTNF/3T3-induced suppre ssion of TNF-production could not be restored to the normal level. It thus seems possible that proTNF might act on macrophages as a bidirect ional regulator of its production by THP-1 cells depending on co-induc ed signals. (C) 1998 Academic Press Limited.