title: 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.affiliation: Department for Molecular Biomedical Research, VIB, Ghent, Belgium.
authors.forename: Sofie
authors.initials: S
authors.lastname: Vandevyver
authors.forename: Lien
authors.initials: L
authors.lastname: Dejager
authors.forename: Tom
authors.initials: T
authors.lastname: Van Bogaert
authors.forename: Anna
authors.initials: A
authors.lastname: Kleyman
authors.forename: Yusen
authors.initials: Y
authors.lastname: Liu
authors.forename: Jan
authors.initials: J
authors.lastname: Tuckermann
authors.forename: Claude
authors.initials: C
authors.lastname: Libert
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D054638:Dual Specificity Phosphatase 1; D004790:Enzyme Induction / Q000187:drug effects / Q000235:genetics; D007249:Inflammation / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism* / Q000473:pathology; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D048688:MAP Kinase Kinase 7 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics; D055503:Protein Multimerization; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000009:adverse effects* / Q000378:metabolism / Q000494:pharmacology
chemical_list: D011965:Receptors, Glucocorticoid; D014409:Tumor Necrosis Factor-alpha; D048688:MAP Kinase Kinase 7; C482570:Map2k7 protein, mouse; D054638:Dual Specificity Phosphatase 1; C517020:Dusp1 protein, mouse