Based on the hypothesis that 26 kD membrane-bound rumor necrosis factor precursor (proTNF) may act as a principle regulator to maintain homeostasis in an adult, we tried to examine whether proTNF shows bidirectional regulation in specific cellular response. We focused on production of 17 kD mature TNF by acute monocytic leukemia cells THP-1 after stimulation by lipopolysaccharide. ProTNF of primed THP-1 cells had been shown to act as a positive regulator for production of mature TNF by homologous cells (primed THP-1) after LPS stimulation, whereas when THP-1 cells were co-cultivated with NIH3T3 which expressed pro-TNF, production of mature TNF by THP-1 by LPS was significantly suppressed. These results suggested that pro-TNF was really involved in bidirectional feedback regulation for TNF production by THP-1 cells themselves through cell to cell contact.