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Glucocorticoid receptor dimerization induces MKP1 to protect against TNF-induced inflammation

Sofie Vandevyver UGent, Lien Dejager UGent, Tom Van Bogaert UGent, Anna Kleyman, Yusen Liu, Jan Tuckermann and Claude Libert UGent (2012) JOURNAL OF CLINICAL INVESTIGATION. 122(6). p.2130-2140
abstract
Glucocorticoids acting through the glucocorticoid receptor (GR) inhibit TNF-induced lethal inflammation. Here, we demonstrate that GR dimerization plays a role in reducing TNF sensitivity. In mutant mice unable to dimerize GR, we found that TNF failed to induce MAPK phosphatase 1 (MKP1). We assessed TNF sensitivity in Mkp1(-/-) mice and found increased inflammatory gene induction in livers, increased circulating cytokines, cell death in intestinal epithelium, severe intestinal inflammation, hypothermia, and death. Mkp1(-/-) mice had increased levels of phosphorylated JNK, which promotes apoptosis, in liver tissue. We further examined JNK-deficient mice for their response to TNF. Although Jnk1(-/-) mice showed no change in sensitivity to TNF, Jnk2(-/-) mice were significantly protected against TNF, identifying JNK2 as an essential player in inflammation induced by TNF. Furthermore, we found that loss of Jnk2 partially rescued the increased sensitivity of Mkp1(-/-) and mutant GR mice to TNF. Our data show that GR dimerization inhibits JNK2 through MKP1 and protects from TNF-induced apoptosis and lethal inflammation.
Please use this url to cite or link to this publication:
author
organization
year
type
journalArticle (original)
publication status
published
subject
keyword
DNA-BINDING, BARRIER DYSFUNCTION, MAP KINASE, NF-KAPPA-B, DUAL-SPECIFICITY PHOSPHATASE-1, TUMOR-NECROSIS-FACTOR, ALPHA, MOUSE, SHOCK, MICE
journal title
JOURNAL OF CLINICAL INVESTIGATION
J. Clin. Invest.
volume
122
issue
6
pages
2130 - 2140
Web of Science type
Article
Web of Science id
000304736300021
JCR category
MEDICINE, RESEARCH & EXPERIMENTAL
JCR impact factor
12.812 (2012)
JCR rank
4/119 (2012)
JCR quartile
1 (2012)
ISSN
0021-9738
DOI
10.1172/JCI60006
language
English
UGent publication?
yes
classification
A1
copyright statement
I have transferred the copyright for this publication to the publisher
id
2941058
handle
http://hdl.handle.net/1854/LU-2941058
date created
2012-06-28 11:06:38
date last changed
2012-07-09 16:22:21
@article{2941058,
  abstract     = {Glucocorticoids acting through the glucocorticoid receptor (GR) inhibit TNF-induced lethal inflammation. Here, we demonstrate that GR dimerization plays a role in reducing TNF sensitivity. In mutant mice unable to dimerize GR, we found that TNF failed to induce MAPK phosphatase 1 (MKP1). We assessed TNF sensitivity in Mkp1(-/-) mice and found increased inflammatory gene induction in livers, increased circulating cytokines, cell death in intestinal epithelium, severe intestinal inflammation, hypothermia, and death. Mkp1(-/-) mice had increased levels of phosphorylated JNK, which promotes apoptosis, in liver tissue. We further examined JNK-deficient mice for their response to TNF. Although Jnk1(-/-) mice showed no change in sensitivity to TNF, Jnk2(-/-) mice were significantly protected against TNF, identifying JNK2 as an essential player in inflammation induced by TNF. Furthermore, we found that loss of Jnk2 partially rescued the increased sensitivity of Mkp1(-/-) and mutant GR mice to TNF. Our data show that GR dimerization inhibits JNK2 through MKP1 and protects from TNF-induced apoptosis and lethal inflammation.},
  author       = {Vandevyver, Sofie and Dejager, Lien and Van Bogaert, Tom and Kleyman, Anna and Liu, Yusen and Tuckermann, Jan and Libert, Claude},
  issn         = {0021-9738},
  journal      = {JOURNAL OF CLINICAL INVESTIGATION},
  keyword      = {DNA-BINDING,BARRIER DYSFUNCTION,MAP KINASE,NF-KAPPA-B,DUAL-SPECIFICITY PHOSPHATASE-1,TUMOR-NECROSIS-FACTOR,ALPHA,MOUSE,SHOCK,MICE},
  language     = {eng},
  number       = {6},
  pages        = {2130--2140},
  title        = {Glucocorticoid receptor dimerization induces MKP1 to protect against TNF-induced inflammation},
  url          = {http://dx.doi.org/10.1172/JCI60006},
  volume       = {122},
  year         = {2012},
}

Chicago
Vandevyver, Sofie, Lien Dejager, Tom Van Bogaert, Anna Kleyman, Yusen Liu, Jan Tuckermann, and Claude Libert. 2012. “Glucocorticoid Receptor Dimerization Induces MKP1 to Protect Against TNF-induced Inflammation.” Journal of Clinical Investigation 122 (6): 2130–2140.
APA
Vandevyver, S., Dejager, L., Van Bogaert, T., Kleyman, A., Liu, Y., Tuckermann, J., & Libert, C. (2012). Glucocorticoid receptor dimerization induces MKP1 to protect against TNF-induced inflammation. JOURNAL OF CLINICAL INVESTIGATION, 122(6), 2130–2140.
Vancouver
1.
Vandevyver S, Dejager L, Van Bogaert T, Kleyman A, Liu Y, Tuckermann J, et al. Glucocorticoid receptor dimerization induces MKP1 to protect against TNF-induced inflammation. JOURNAL OF CLINICAL INVESTIGATION. 2012;122(6):2130–40.
MLA
Vandevyver, Sofie, Lien Dejager, Tom Van Bogaert, et al. “Glucocorticoid Receptor Dimerization Induces MKP1 to Protect Against TNF-induced Inflammation.” JOURNAL OF CLINICAL INVESTIGATION 122.6 (2012): 2130–2140. Print.