TY - JOUR
T1 - STAT4-mediated transcriptional repression of the IL5 gene in human memory Th2 cells
AU - Gonzales-van Horn, Sarah R.
AU - Estrada, Leonardo D.
AU - van Oers, Nicolai S C
AU - Farrar, J. David
N1 - Publisher Copyright:
© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
PY - 2016/6/1
Y1 - 2016/6/1
N2 - Type I interferon (IFN-α/β) plays a critical role in suppressing viral replication by driving the transcription of hundreds of interferon-sensitive genes (ISGs). While many ISGs are transcriptionally activated by the ISGF3 complex, the significance of other signaling intermediates in IFN-α/β-mediated gene regulation remains elusive, particularly in rare cases of gene silencing. In human Th2 cells, IFN-α/β signaling suppressed IL5 and IL13 mRNA expression during recall responses to T-cell receptor (TCR) activation. This suppression occurred through a rapid reduction in the rate of nascent transcription, independent of de novo expression of ISGs. Further, IFN-α/β-mediated STAT4 activation was required for repressing the human IL5 gene, and disrupting STAT4 dimerization reversed this effect. This is the first demonstration of STAT4 acting as a transcriptional repressor in response to IFN-α/β signaling and highlights the unique activity of this cytokine to acutely block the expression of an inflammatory cytokine in human T cells.
AB - Type I interferon (IFN-α/β) plays a critical role in suppressing viral replication by driving the transcription of hundreds of interferon-sensitive genes (ISGs). While many ISGs are transcriptionally activated by the ISGF3 complex, the significance of other signaling intermediates in IFN-α/β-mediated gene regulation remains elusive, particularly in rare cases of gene silencing. In human Th2 cells, IFN-α/β signaling suppressed IL5 and IL13 mRNA expression during recall responses to T-cell receptor (TCR) activation. This suppression occurred through a rapid reduction in the rate of nascent transcription, independent of de novo expression of ISGs. Further, IFN-α/β-mediated STAT4 activation was required for repressing the human IL5 gene, and disrupting STAT4 dimerization reversed this effect. This is the first demonstration of STAT4 acting as a transcriptional repressor in response to IFN-α/β signaling and highlights the unique activity of this cytokine to acutely block the expression of an inflammatory cytokine in human T cells.
KW - CD4 T cells
KW - Cytokines
KW - Gene regulation
KW - IFNs
KW - Transcription factors
UR - http://www.scopus.com/inward/record.url?scp=84973626854&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84973626854&partnerID=8YFLogxK
U2 - 10.1002/eji.201546050
DO - 10.1002/eji.201546050
M3 - Article
C2 - 26990433
AN - SCOPUS:84973626854
SN - 0014-2980
VL - 46
SP - 1504
EP - 1510
JO - European Journal of Immunology
JF - European Journal of Immunology
IS - 6
ER -