TY - JOUR
T1 - BTB-ZF transcriptional regulator PLZF modifies chromatin to restrain inflammatory signaling programs
AU - Sadler, Anthony John
AU - Rossello, Fernando Jaime
AU - Yu, Liang
AU - Deane, James Antony
AU - Yuan, Xiang-Liang
AU - Wang, Die
AU - Irving, Aaron Trent
AU - Liaskos, Maria
AU - Gantier, Michael Paul Marie
AU - Ying, Hangjie
AU - Yim, Howard Chi Ho
AU - Hartland, Elizabeth Louise
AU - Notini, Amanda Jill
AU - De Boer, Carmela Maria
AU - White, Stefan
AU - Mansell, Ashley Scott
AU - Liu, Jun-Ping
AU - Watkins, David Neil
AU - Gerondakis, Steven Demetrious
AU - Williams, Bryan Raymond George
AU - Xu, Dakang
PY - 2015
Y1 - 2015
N2 - Inflammation is critical for host defense, but without appropriate control, it can cause chronic disease or even provoke fatal responses. Here we identify a mechanism that limits the inflammatory response. Probing the responses of macrophages to the key sensory Toll-like receptors, we identify that the Broad-complex, Tramtrack and Bric-a-brac/poxvirus and zinc finger (BTB/POZ), transcriptional regulator promyelocytic leukemia zinc finger (PLZF) limits the expression of inflammatory gene products. In accord with this finding, PLZF-deficient animals express higher levels of potent inflammatory cytokines and mount exaggerated inflammatory responses to infectious stimuli. Temporal quantitation of inflammatory gene transcripts shows increased gene induction in the absence of PLZF. Genome-wide analysis of histone modifications distinguish that PLZF establishes basal activity states of early response genes to maintain immune homeostasis and limit damaging inflammation. We show that PLZF stabilizes a corepressor complex that encompasses histone deacetylase activity to control chromatin. Together with our previous demonstration that PLZF promotes the antiviral response, these results suggest a strategy that could realize one of the major goals of immune therapy to retain immune resistance to pathogens while curbing damaging inflammation.
AB - Inflammation is critical for host defense, but without appropriate control, it can cause chronic disease or even provoke fatal responses. Here we identify a mechanism that limits the inflammatory response. Probing the responses of macrophages to the key sensory Toll-like receptors, we identify that the Broad-complex, Tramtrack and Bric-a-brac/poxvirus and zinc finger (BTB/POZ), transcriptional regulator promyelocytic leukemia zinc finger (PLZF) limits the expression of inflammatory gene products. In accord with this finding, PLZF-deficient animals express higher levels of potent inflammatory cytokines and mount exaggerated inflammatory responses to infectious stimuli. Temporal quantitation of inflammatory gene transcripts shows increased gene induction in the absence of PLZF. Genome-wide analysis of histone modifications distinguish that PLZF establishes basal activity states of early response genes to maintain immune homeostasis and limit damaging inflammation. We show that PLZF stabilizes a corepressor complex that encompasses histone deacetylase activity to control chromatin. Together with our previous demonstration that PLZF promotes the antiviral response, these results suggest a strategy that could realize one of the major goals of immune therapy to retain immune resistance to pathogens while curbing damaging inflammation.
UR - http://www.pnas.org/content/112/5/1535.full.pdf
U2 - 10.1073/pnas.1409728112
DO - 10.1073/pnas.1409728112
M3 - Article
SN - 0027-8424
VL - 112
SP - 1535
EP - 1540
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 5
ER -