TNFα and TGF-β1 influence IL-18-induced IFNγ production through regulation of IL-18 receptor and T-bet expression

Bacterial infections can lead to a state of uncontrolled inflammation and also trigger autoimmune disease. At the centre of this are CD4+ T cell responses in inflammatory tissues or local lymph nodes which are orchestrated by dendritic cells. IL-18 is a pro-inflammatory cytokine that drives dendritic cell maturation and mediates IFNγ production. In this study, we demonstrate that in the dendritic precursor-like cell line KG-1, IFNγ production induced by IL-18 is potentiated (>5-fold) by TNFα and completely suppressed by TGF-β1. IL-18 stimulation rapidly activates different MAPK signalling pathways but only blocking of p38 activation alleviates IFNγ production. The mechanism through which TNFα enhances IL-18 induced IFNγ production is by promoting IL-18 receptor α-chain expression which results in higher levels of p38 activation and induces expression of T-bet, a transcriptional regulator of the IFNG gene. In contrast, TGF-β1 rapidly suppresses IFNγ production by limiting IL-18 receptor numbers at the cell surface and preventing induction of T-bet expression. TGF-β1 experience by cells leads to sustained long-term inactivation of TNFα/IL-18-mediated cell activation but not IL-18 induced p38 activation suggesting transcriptional silencing of the T-BET and/or IFNG promoter independent of MAPK signalling. These results demonstrate how IL-18 activity is regulated by pro and anti-inflammatory cytokines and thereby provide insight into the mechanism that controls dendritic cell activity and ultimately leads to resolution of an inflammatory response.