We investigated the molecular basis of the synergistic induction by interferon- (IFN-)/tumor necrosis factor- (TNF-) of human interleukin-6 (IL-6) gene in THP-1 monocytic cells, and compared it with the basis of this induction by lipopolysaccharide (LPS). Functional studies with IL-6 promoter demonstrated that three regions are the targets of the IFN- and/or TNF- action, whereas only one of these regions seemed to be implicated in LPS activation. The three regions concerned are: 1) a region between -73 and -36, which is the minimal element inducible by LPS or TNF-; 2) an element located between -181 and -73, which appeared to regulate the response to IFN- and TNF- negatively; and 3) a distal element upstream of -224, which was inducible by IFN- alone. LPS signaling was found to involve NFB activation by the p50/p65 heterodimers. Synergistic induction of the IL-6 gene by IFN- and TNF-, in monocytic cells, involved cooperation between the IRF-1 and NFB p65 homodimers with concomitant removal of the negative effect of the retinoblastoma control element present in the IL-6 promoter. This removal occurred by activation of the constitutive Sp1 factor, whose increased binding activity and phosphorylation were mediated by IFN-.

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