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

@article{citeulike:6065143, 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 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.}, author = {Koutoulaki, Anna and Langley, Martin and Sloan, Alastair J. and Aeschlimann, Daniel and Wei, Xiao-Qing}, citeulike-article-id = {6065143}, citeulike-linkout-0 = {http://dx.doi.org/10.1016/j.cyto.2009.09.015}, citeulike-linkout-1 = {http://linkinghub.elsevier.com/retrieve/pii/S1043466609008369}, day = {30}, doi = {10.1016/j.cyto.2009.09.015}, issn = {10434666}, journal = {Cytokine}, keywords = {ifn-gamma, il-18, mapk, tnf}, month = {October}, posted-at = {2009-11-08 22:55:01}, priority = {2}, title = {TNFα and TGF-β1 influence IL-18-induced IFNγ production through regulation of IL-18 receptor and T-bet expression}, url = {http://dx.doi.org/10.1016/j.cyto.2009.09.015}, year = {2009} }

TY - JOUR ID - citeulike:6065143 L3 - citeulike-article-id:6065143 N2 - 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. JF - Cytokine SN - 10434666 TI - TNFα and TGF-β1 influence IL-18-induced IFNγ production through regulation of IL-18 receptor and T-bet expression KW - ifn-gamma KW - il-18 KW - mapk KW - tnf AU - Koutoulaki, Anna AU - Langley, Martin AU - Sloan, Alastair AU - Aeschlimann, Daniel AU - Wei, Xiao-Qing PY - 2009/10/30/ UR - http://dx.doi.org/10.1016/j.cyto.2009.09.015 ER -