Glucocorticoid receptor dimerization induces MKP1 to protect against TNF-induced inflammation
Sofie Vandevyver, Lien Dejager, Tom Van Bogaert, Anna Kleyman, Yusen Liu, Jan Tuckermann, Claude Libert
Sofie Vandevyver, Lien Dejager, Tom Van Bogaert, Anna Kleyman, Yusen Liu, Jan Tuckermann, Claude Libert
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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 5

Mkp1–/–Jnk2–/– mice show reduced sensitivity to TNF.

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Mkp1–/–Jnk2–/– mice show reduced sensitivity to TNF. (A) Survival of ...
(A) Survival of Mkp1+/+Jnk2+/+ (black squares; n = 22), Mkp1–/– (gray circles; n = 34), and Mkp1–/–Jnk2–/– (white squares; n = 24) mice after i.p. injection of 5 μg TNF. *P < 0.05, ***P < 0.001 vs. control; **P < 0.01, Mkp1–/–Jnk2–/– vs. Mkp1–/–. (B) Body temperature of mice as in A. **P < 0.01, ***P < 0.001. (C) Serum IL-6 concentrations and liver Il6 mRNA levels 0, 1, and 6 hours after challenge with 5 μg TNF (n = 5 per group). (D) Standard H&E staining of ileum samples (n = 5 per group). The ileum was sampled 0 and 1 hour after i.p. injection of 5 μg TNF. The micrograph at 0 hour is representative of all genotypes. Scale bars: 100 μm. Original magnification, ×40. (C and D) *P < 0.05, **P < 0.01, ***P < 0.001 vs. 0 hours or as indicated by brackets. (B–D) Black bars, Mkp1+/+Jnk2+/+; white bars, Mkp1–/–Jnk2–/–; gray bars, Mkp1–/–. (E and F) Survival (E) and body temperature (F) of GRwt/wtJnk2+/+ (black bars and symbols; n = 7), GRdim/dim (gray bars and gray circles; n = 5), and GRdim/dimJnk2–/– (white bars and white squares; n = 3) mice after i.p. injection of 20 μg TNF. *P < 0.05, **P < 0.01, ***P < 0.001.