TNFa and TGF-b1 influence IL-18-induced IFNg 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 super(+) 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 IFNg production. In this study, we demonstrate that in the dendritic precursor-like cell line KG-1, IFNg production induced by IL-18 is potentiated (>5-fold) by TNFa and completely suppressed by TGF-b1. IL-18 stimulation rapidly activates different MAPK signalling pathways but only blocking of p38 activation alleviates IFNg production. The mechanism through which TNFa enhances IL-18 induced IFNg production is by promoting IL-18 receptor a-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-b1 rapidly suppresses IFNg production by limiting IL-18 receptor numbers at the cell surface and preventing induction of T-bet expression. TGF-b1 experience by cells leads to sustained long-term inactivation of TNFa/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.