Glucocorticoid receptor dimerization induces MKP1 to protect against TNF-induced inflammation
Sofie Vandevyver, … , Jan Tuckermann, Claude Libert
Sofie Vandevyver, … , Jan Tuckermann, Claude Libert
Published May 15, 2012
Citation Information: J Clin Invest. 2012;122(6):2130-2140. https://doi.org/10.1172/JCI60006.
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Research Article Immunology

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

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.

Authors

Sofie Vandevyver, Lien Dejager, Tom Van Bogaert, Anna Kleyman, Yusen Liu, Jan Tuckermann, Claude Libert

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Figure 3

JNK phosphorylation in liver is higher in Mkp1–/– and GRdim/dim mice.

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JNK phosphorylation in liver is higher in Mkp1–/– and GRdim/dim mice. ...
(A) Western blot analysis of phospho-JNK1/2 protein levels in livers of Mkp1+/+ and Mkp1–/– mice. Mice were injected i.p. with 5 μg TNF, and livers were harvested at the indicated times after challenge. The phospho-JNK1/2 bands (46 kDa and 54 kDa) were normalized to the intensities of the total JNK1/2 and actin bands (42 kDa). Black bars, Mkp1+/+; white bars, Mkp1–/–. (B) Western blot analysis of phospho-JNK1/2 protein levels in livers of GRwt/wt and GRdim/dim mice. Mice were treated with 25 μg TNF; 0 and 0.5 hours later, they were euthanized, and livers were obtained for Western blot analysis. Normalized values are also shown. Black bars, GRwt/wt; white bars, GRdim/dim. (A and B) *P < 0.05, **P < 0.01, ***P < 0.001 vs. 0 hours or as indicated by brackets. See complete unedited blots in the supplemental material.