Control by IFN-γ and PGE₂ of TNFα and IL-1 production by human monocytes

There have been suggestions that the production of pro-inflammatory mediators by human monocytes in response to interferon-gamma (IFN-γ) may be controlled by changes in prostaglandins. Therefore we investigated tumour necrosis factor α (TNFα) and interleukin-1 (IL-1) activities and prostaglandin E₂ (PGE₂) levels in the supernatants of highly purified human monocytes cultured for 18 hr with recombinant human IFN-γ. IFN-γ (100 U/ml) did not stimulate monocytes isolated by counter-current centrifugal elutriation for detectable TNFα or IL-1 activities, or PGE₂ production. However, IFN-γ synergistically enhanced lipopolysaccharide (LPS)-induced TNFα and IL-1 activities. In contrast, there was no consistent change in PGE₂ levels upon addition of IFN-γ to LPS-treated monocyte cultures. The TNFα and IL-1 activities induced by LPS and by LPS with IFN-γ were reduced by PGE₂, and stimulated by indomethacin. As reported previously for IL-1 activities, the regulation by cyclo-oxygenase products of TNFα activities reflected predominantly a control of the production of immunoreactive TNFα, rather than the measurement of TNFα bio-activity. However, the addition of indomethacin or PGE₂ to monocyte cultures did not change the extent of IFN-γ synergy with LPS for increased TNFα and IL-1 activities. The results of this study suggest that, despite control by cyclo-oxygenase products of TNFα and IL-1 production in human monocytes, IFN-γ may enhance TNFα and IL-1 activities independently of this regulatory mechanism. These findings are contrary to those suggested for the regulation by prostanoids of IL-1 production by murine macrophages.