TY - JOUR
T1 - Tle1 tumor suppressor negatively regulates inflammation in vivo and modulates NF-κB inflammatory pathway
AU - Ramasamy, Selvi
AU - Saez, Borja
AU - Mukhopadhyay, Subhankar
AU - Ding, Daching
AU - Ahmed, Alwiya M.
AU - Chen, Xi
AU - Pucci, Ferdinando
AU - Yamin, Rae'e
AU - Wang, Jianfeng
AU - Pittet, Mikael J.
AU - Kelleher, Cassandra M.
AU - Scadden, David T.
AU - Sweetser, David A.
N1 - Funding Information:
The authors acknowledge Dr. Mari Mino-Kenudson of Massachusetts General Hospital, Pathology Department for help with interpreting histology slides as well as Katherine Folz-Donohue, Laura Prickett-Rice, Meredith Weglarz, and David Dombkowski for their assistance with flow cytometry. This work was supported by National Institutes of Health Grant R01 CA115772 (to S.R., D.D., X.C., and D.A.S.), Alex''s Lemonade Stand Foundation (S.R.), MGH Marathon Fund (D.A.S.), and Swim Across America (D.A.S.).
PY - 2016/2/16
Y1 - 2016/2/16
N2 - Tle1 (transducin-like enhancer of split 1) is a corepressor that interacts with a variety of DNA-binding transcription factors and has been implicated in many cellular functions; however, physiological studies are limited. Tle1-deficient (Tle1Δ/Δ) mice, although grossly normal at birth, exhibit skin defects, lung hypoplasia, severe runting, poor body condition, and early mortality. Tle1Δ/Δ mice display a chronic inflammatory phenotype with increased expression of inflammatory cytokines and chemokines in the skin, lung, and intestine and increased circulatory IL-6 and G-CSF, along with a hematopoietic shift toward granulocyte macrophage progenitor and myeloid cells. Tle1Δ/Δ macrophages produce increased inflammatory cytokines in response to Toll-like receptor (TLR) agonists and lipopolysaccharides (LPS), and Tle1Δ/Δ mice display an enhanced inflammatory response to ear skin 12-O-tetradecanoylphorbol-13-acetate treatment. Loss of Tle1 not only results in increased phosphorylation and activation of proinflammatory NF-κB but also results in decreased Hes1 (hairy and enhancer of split-1), a negative regulator of inflammation in macrophages. Furthermore, Tle1Δ/Δ mice exhibit accelerated growth of B6-F10 melanoma xenografts. Our work provides the first in vivo evidence, to our knowledge, that TLE1 is a major counterregulator of inflammation with potential roles in a variety of inflammatory diseases and in cancer progression.
AB - Tle1 (transducin-like enhancer of split 1) is a corepressor that interacts with a variety of DNA-binding transcription factors and has been implicated in many cellular functions; however, physiological studies are limited. Tle1-deficient (Tle1Δ/Δ) mice, although grossly normal at birth, exhibit skin defects, lung hypoplasia, severe runting, poor body condition, and early mortality. Tle1Δ/Δ mice display a chronic inflammatory phenotype with increased expression of inflammatory cytokines and chemokines in the skin, lung, and intestine and increased circulatory IL-6 and G-CSF, along with a hematopoietic shift toward granulocyte macrophage progenitor and myeloid cells. Tle1Δ/Δ macrophages produce increased inflammatory cytokines in response to Toll-like receptor (TLR) agonists and lipopolysaccharides (LPS), and Tle1Δ/Δ mice display an enhanced inflammatory response to ear skin 12-O-tetradecanoylphorbol-13-acetate treatment. Loss of Tle1 not only results in increased phosphorylation and activation of proinflammatory NF-κB but also results in decreased Hes1 (hairy and enhancer of split-1), a negative regulator of inflammation in macrophages. Furthermore, Tle1Δ/Δ mice exhibit accelerated growth of B6-F10 melanoma xenografts. Our work provides the first in vivo evidence, to our knowledge, that TLE1 is a major counterregulator of inflammation with potential roles in a variety of inflammatory diseases and in cancer progression.
KW - HES1
KW - Inflammation
KW - NF-κB
KW - TLE1
KW - Tumor suppressor
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U2 - 10.1073/pnas.1511380113
DO - 10.1073/pnas.1511380113
M3 - Article
C2 - 26831087
AN - SCOPUS:84959036636
SN - 0027-8424
VL - 113
SP - 1871
EP - 1876
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 - 7
ER -