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.

Glucocorticoid receptor inhibits Müller glial galectin‐1 expression via DUSP1‐dependent and ‐independent deactivation of AP‐1 signalling

“…DUSP1, a glucocorticoid‐transactivated phosphatase localized in the nucleus, exerts anti‐inflammatory function through dephosphorylation of activated signalling molecules such as ERK1/2 and p38 MAPKs and AKT . Given that Dusp1 ‐deficient mice exhibited enhanced inflammatory response and energy expenditure, DUSP1 is an essential component for maintaining intracellular homoeostasis that controls the threshold and magnitude of signal transduction. In consistence with our human tissue data (Figure ), DUSP1 was reported to exist in rat retinal cells including Müller glial cells and work as a suppressive regulator of inflammation in bovine Müller glial cells .…”

The five Rs of glucocorticoid action during inflammation: ready, reinforce, repress, resolve, and restore

“…The induction of MAPK phosphatase-1 prevents the phosphorylation and activation of JNK [55-58]. Although initial evidence suggested that glucocorticoids could induce the expression of IκBα to sequester p65/p50 in the cytoplasm, this response seems to be cellspecific and is not a universal mechanism to regulate NF-κB signaling [59].…”

Nuclear receptors in inflammation control: Repression by GR and beyond

“…, BRG1 (Burd, et al 2012; Trotter and Archer 2008). Several GR-induced genes encode anti-inflammatory molecules such as Dusp1 (Imasato, et al 2002; Vandevyver, et al 2012), Tsc22d3 (GILZ) (Cannarile, et al 2009; Mittelstadt and Ashwell 2001) and IκB (Scheinman, et al 1995a). The role of these factors in inflammation is beyond the scope of this review and has been extensively discussed elsewhere (Clark 2007).…”