TNFalpha and TGF-beta1 influence IL-18-induced IFNgamma 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 IFNgamma production. In this study, we demonstrate that in the dendritic precursor-like cell line KG-1, IFNgamma production induced by IL-18 is potentiated (>5-fold) by TNFalpha and completely suppressed by TGF-beta1. IL-18 stimulation rapidly activates different MAPK signalling pathways but only blocking of p38 activation alleviates IFNgamma production. The mechanism through which TNFalpha enhances IL-18 induced IFNgamma 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-beta1 rapidly suppresses IFNgamma production by limiting IL-18 receptor numbers at the cell surface and preventing induction of T-bet expression. TGF-beta1 experience by cells leads to sustained long-term inactivation of TNFalpha/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.
Koutoulaki
Anna
A
Tissue Engineering and Reparative Dentistry, School of Dentistry, Cardiff University, Heath Park, Cardiff CF14 4XY, UK.
Langley
Martin
M
Sloan
Alastair J
AJ
Aeschlimann
Daniel
D
Wei
Xiao-Qing
XQ
D002460:Cell Line; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000378:metabolism; D006801:Humans; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology*; D020382:Interleukin-18 / Q000235:genetics / Q000276:immunology*; D020935:MAP Kinase Signaling System / Q000502:physiology; D053724:Receptors, Interleukin-18 / Q000235:genetics / Q000276:immunology*; D020825:T-Box Domain Proteins / Q000235:genetics / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000098815:T-bet Transcription Factor
D004791:Enzyme Inhibitors; D020382:Interleukin-18; D053724:Receptors, Interleukin-18; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D048051:p38 Mitogen-Activated Protein Kinases