TNF alpha and TGF-beta 1 influence IL-18-induced IFN gamma production through regulation of IL-18 receptor and T-bet expression

Koutoulaki, Anna, Langley, Martin Simon, Sloan, Alastair James ORCID: https://orcid.org/0000-0002-1791-0903, Aeschlimann, Daniel ORCID: https://orcid.org/0000-0003-0930-7706 and Wei, Xiao-Qing ORCID: https://orcid.org/0000-0002-6274-8503 2010. TNF alpha and TGF-beta 1 influence IL-18-induced IFN gamma production through regulation of IL-18 receptor and T-bet expression. Cytokine 49 (2) , pp. 177-184. 10.1016/j.cyto.2009.09.015

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Abstract

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 IFN gamma production. in this study, we demonstrate that in the dendritic precursor-like cell line KG-1, IFN gamma production induced by IL-18 is potentiated (>5-fold) by TNF alpha and completely suppressed by TGF-beta 1. IL-18 stimulation rapidly activates different MAN signalling pathways but only blocking of p38 activation alleviates IFN gamma production. The mechanism through which TNF alpha enhances IL-18 induced IFN-gamma production is by promoting IL-18 receptor alpha-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-beta 1 rapidly suppresses IFN gamma production by limiting IL-18 receptor numbers at the cell surface and preventing induction of T-bet expression. TGF-beta 1 experience by cells leads to sustained long-term inactivation of TNF alpha/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 MAN signalling. These results demonstrate how IL-1 8 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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Dentistry
Uncontrolled Keywords:	Human; Dendritic cell; KG-1 cell line; IL-18; Inflammation
Publisher:	Elsevier
ISSN:	1043-4666
Last Modified:	18 Oct 2022 13:55
URI:	https://orca.cardiff.ac.uk/id/eprint/15916

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