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

(2012) JOURNAL OF CLINICAL INVESTIGATION. 122(6). p.2130-2140
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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.
Keywords
DNA-BINDING, BARRIER DYSFUNCTION, MAP KINASE, NF-KAPPA-B, DUAL-SPECIFICITY PHOSPHATASE-1, TUMOR-NECROSIS-FACTOR, ALPHA, MOUSE, SHOCK, MICE

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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.
@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},
}

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