A synergistic role for IL-1β and TNFα in monocyte-derived IFNγ inducing activity

Although much is known about classic IFNγ inducers, little is known about the IFNγ inducing capability of inflammasome-activated monocytes. In this study, supernatants from LPS/ATP-stimulated human monocytes were analyzed for their ability to induce IFNγ production by KG-1 cells. Unexpectedly, monocyte-derived IFN inducing activity was detected, but it was completely inhibited by IL-1β, not IL-18 blockade. Moreover, size-fractionation of the monocyte conditioned media dramatically reduced the IFNγ inducing activity of IL-1β, suggesting that IL-1β requires a cofactor to induce IFNγ production in KG-1 cells. Because TNFα is known to synergize with IL-1β for various gene products, it was studied as the putative IL-1β synergizing factor. Although recombinant TNFα (rTNFα) alone had no IFNγ inducing activity, neutralization of TNFα in the monocyte conditioned media inhibited the IFNγ inducing activity. Furthermore, rTNFα restored the IFNγ inducing activity of the size-fractionated IL-1β. Finally, rTNFα synergized with rIL-1β, as well as with rIL-1α and rIL-18, for KG-1 IFNγ release. These studies demonstrate a synergistic role between TNFα and IL-1 family members in the induction of IFNγ production and give caution to interpretations of KG-1 functional assays designed to detect functional IL-18.